U.S. patent number 5,605,896 [Application Number 08/299,188] was granted by the patent office on 1997-02-25 for bicyclic heterocyclic derivatives having .alpha..sub.1 adrenergic and 5ht.sub.1a activities.
This patent grant is currently assigned to Recordati S.A., Chemical and Pharmaceutical Company. Invention is credited to Amedeo Leonardi, Gianni Motta, Carlo Riva, Rodolfo Testa.
United States Patent |
5,605,896 |
Leonardi , et al. |
February 25, 1997 |
**Please see images for:
( Certificate of Correction ) ** |
Bicyclic heterocyclic derivatives having .alpha..sub.1 adrenergic
and 5HT.sub.1A activities
Abstract
This invention provides bicyclic heterocyclic derivatives and
their pharmaceutically acceptable salts useful for the treatment of
hypertension, urethral and lower urinary tract contractions, and
other disorders. The compounds are also useful for binding
.alpha..sub.1 -adrenergic and 5HT.sub.1A serotonergic receptors, in
vitro or in vivo.
Inventors: |
Leonardi; Amedeo (Milan,
IT), Motta; Gianni (Barlassina, IT), Riva;
Carlo (Varese, IT), Testa; Rodolfo (Milan,
IT) |
Assignee: |
Recordati S.A., Chemical and
Pharmaceutical Company (Chiasso, CH)
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Family
ID: |
27442645 |
Appl.
No.: |
08/299,188 |
Filed: |
August 31, 1994 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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67861 |
May 26, 1993 |
5474994 |
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888775 |
May 26, 1992 |
5403842 |
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Foreign Application Priority Data
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Feb 25, 1992 [IT] |
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MI92A0408 |
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Current U.S.
Class: |
514/218;
514/232.2; 514/233.5; 514/234.5; 514/252.13; 514/253.07;
514/253.08; 514/254.11; 514/314; 514/394; 514/414; 514/443;
514/452; 514/456; 514/469; 540/575; 544/143; 544/144; 544/146;
544/148; 544/151; 544/153; 544/363; 544/373; 544/376; 544/377;
546/121; 546/153; 546/169; 546/170; 546/174; 546/175; 546/176;
546/196; 546/202; 546/204; 548/304.4; 548/491; 549/23; 549/362;
549/398; 549/401; 549/403; 549/405; 549/49 |
Current CPC
Class: |
C07D
307/79 (20130101); C07D 307/80 (20130101); C07D
311/22 (20130101); C07D 311/30 (20130101); C07D
311/32 (20130101); C07D 311/60 (20130101); C07D
335/06 (20130101); C07D 405/04 (20130101); C07D
405/12 (20130101); C07D 407/12 (20130101); C07D
409/04 (20130101); C07F 9/65586 (20130101) |
Current International
Class: |
C07D
405/04 (20060101); C07D 407/00 (20060101); C07D
407/12 (20060101); C07D 405/00 (20060101); C07D
307/00 (20060101); C07D 405/12 (20060101); C07D
311/00 (20060101); C07D 307/80 (20060101); C07D
307/79 (20060101); C07D 311/22 (20060101); C07D
311/60 (20060101); C07D 409/04 (20060101); C07D
409/00 (20060101); C07D 311/32 (20060101); C07D
311/30 (20060101); C07D 335/06 (20060101); C07D
335/00 (20060101); C07F 9/00 (20060101); C07F
9/6558 (20060101); C07D 243/08 (); C07D 413/00 ();
C07D 215/16 (); C07D 235/04 (); A61K 031/395 ();
A61K 031/47 (); A61K 031/38 (); A61K 031/335 () |
Field of
Search: |
;540/575
;544/143,144,146,148,151,153,363,373,376,377
;546/153,169,170,121,176,174,175,196,202,204 ;548/304.4,991
;549/23,49,362,398,401,403,405
;514/218,234.5,232.2,233.5,253,314,414,443,452,394,456,469 |
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|
WO |
|
WO95/05169 |
|
Feb 1995 |
|
WO |
|
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Primary Examiner: Grumbling; Matthew V.
Attorney, Agent or Firm: Darby & Darby
Parent Case Text
This is a continuation-in-part of U.S. patent application Ser. No.
08/067,861 filed May 26, 1993 now U.S. Pat. No. 5,474,994 which is
a continuation-in-part of U.S. patent application Ser. No.
07/888,775, filed May 26, 1992 now U.S. Pat. No. 5,403,842. This
invention relates to bicyclic heterocyclic derivatives, to
pharmaceutical compositions containing them and to uses for such
derivatives and compositions.
Claims
We claim:
1. A compound having the general formula I ##STR22## wherein ----
represents a single or double bond;
X represents a nitrogen, oxygen or sulfur atom, an amino or
alkylamino, a sulfinyl or sulfonyl group;
W represents a carbonyl, thiocarbonyl, hydroxymethylene, a
methylene group or a bond; or
X is nitrogen and W is methine, and the fused rings represent
quinolyl ring;
R.sub.2 represents a hydrogen atom or an alkyl, alkenyl, alkynyl,
carbocyclic or heterocyclic group, each of which groups may
optionally be substituted by one or more substituents selected from
the group consisting of alkyl, cyano, hydroxy, alkoxy, halogen,
phenyl, phenoxy, trifluoromethyl, nitro, acylamino,
alkylsulfonylamino and benzoyl; or R.sub.2 itself represents a
trifluoromethyl or an aroyl group; wherein the carbocyclic group
may be substituted with amino, alkylamino or dialkylamino;
with the proviso that the heterocyclic group cannot be linked
through a nitrogen atom;
R.sub.3 represents a hydrogen atom or an alkyl, hydroxyalkyl,
phenyl, hydroxy, O--R.sub.4, or alkyl-OR.sub.4 group, where R.sub.4
represents an alkyl group optionally substituted with an aryl
group;
R.sub.6 represents a hydrogen or halogen atom or a nitro, amino,
acetylamino, alkylamino, dialkylamino, cyano, hydroxy, alkoxy or
alkyl group;
R.sub.7 represents a hydrogen atom;
Y represents one of the following groups, each of which is depicted
with its left hand end being the end which attaches to the
heterobicyclic ring and its right hand end being the end which
attaches to the group Z: ##STR23## Z a linear or branched chain
alkylene group having from 1 to 6 carbon atoms and optionally
having one hydroxy substituent; and
represents one of the following groups: ##STR24## wherein n is 1 or
2 and A represents a phenyl group; wherein said phenyl group is
unsubstituted or substituted by one or more substituents selected
from the group consisting of alkoxy, alkyl, halogen, hydroxy, or A
represents a 2-pyrimidinyl group or a bicyclic ring of formula
##STR25## where ---- represents a single or double bond and E
represents an oxygen atom or a bond; ##STR26## wherein L represents
one or two groups selected among phenyl, 4-fluorobenzoyl or a
2-oxo-1-benzimidozolinyl group or a group of the formula
(CH.sub.2).sub.n -O-A wherein n=0, 1, or 2 and A has the same
meaning defined under B1, ##STR27## wherein each of R.sub.10 and
R.sub.11 independently represents a hydrogen atom or an alkoxy or
alkylthio group, R.sub.12 represents a hydrogen atom or an alkyl
group and n is 2 or 3, ##STR28## wherein R.sub.12 has the meaning
defined under B3 and R.sub.13 represents a hydrogen atom or a
alkoxy group, ##STR29## wherein R.sub.12 has the meaning defined
under B3, or an enantiomer, a diastereomer, an N-oxide, a prodrug,
a metabolite, a prodrug of a metabolite, or a pharmaceutically
acceptable salt of said compound.
2. A compound according to claim 1, wherein Y represents one of the
groups Y2, Y3, Y37, Y40 or Y41.
3. A compound according to claim 1, wherein B is B1 and A is a
phenyl group substituted by one or more substituents.
4. A compound according to claim 1, wherein
---- represents a double bond,
W represents a carbonyl group,
X represents an oxygen atom,
R.sub.2 represents a phenyl group,
R.sub.3 represents a methyl group,
R.sub.6 represents a hydrogen atom, and
R.sub.7 represents a hydrogen atom.
5. A compound according to claim 4, wherein Y represents one of the
groups Y2, Y3, Y37, Y40 or Y41.
6. A compound according to claim 5, wherein Z represents a
trimethylene or tetramethylene group.
7. A compound according to claim 5, wherein B represents one of the
groups B1 or B3.
8. A compound according to claim 6, wherein B represents one of the
groups B1 or B3.
9. A compound according to claim 7, wherein B represents a
4-(2-methoxyphenyl)-1-piperazinyl group.
10. A compound according to claim 8, wherein B represents a
4-(2-methoxyphenyl)-1-piperazinyl group.
11. A compound according to claim 4, wherein B is B3 and at least
one of R.sub.10, R.sub.11 is methoxy.
12. Compound selected from the group consisting of:
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-1-oxoethyl}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran;
8-{2-[4-(2-methylphenyl)-1-piperazinyl]-1-oxoethyl}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran;
8-{2-[4-(2-ethoxyphenyl)-1-piperazinyl]-1-oxoethyl}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran;
8-{3-[4-(2-methoxy-phenyl)-1-piperazinyl]-1-oxopropyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxycarbonyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxycarbonyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-{3-[4-(2-chlorophenyl)-1-piperazinyl]-propoxycarbonyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-[3-(4-phenyl-1-piperazinyl)-propoxycarbonyl]-3-methyl-4-oxo-2-phenyl-4H-1
-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-propoxycarbonyl}-3-meth
yl-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl-carbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{3-[2-(2-methoxyphenoxy)-ethylamino]-propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-[3-(4-phenyl-1-piperazinyl)-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1
-benzopyran;
8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
8-{1-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{1-hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-{1-hydroxy-2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-{1-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-3-methyl-4-oxo-2
-phenyl-4H-1-benzopyran;
8-{1-hydroxy-4-[4-(2-methoxyphenyl)-1-piperazinyl]-butyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{1-ethoxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylaminomethyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran;
8-{N-acetyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylaminomethyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran;
8-[4-(2-methoxyphenyl)-1-piperazinylacetamidomethyl]-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran;
8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-acetamidomethyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxymethyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
8-{2-[2-(2-ethoxyphenoxy)-ethylamino]-ethoxymethyl}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylthiomethyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulfinylmethyl}-3-methyl-4-ox
o-2-phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulfonylmethyl}-3-methyl-4-ox
o-2-phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylamino}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-oxo-2-phen
yl-4H-1-benzopyran;
8-
{4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylamino}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran;
8-{N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran;
8-{N-acetyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propionamido}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylureido}-3-methyl-4-oxo-2-phen
yl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxy}-3-methyl-4-oxo-2-phenyl-4H
-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxy}-3-methyl-4-oxo-2-phenyl-4
H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-butoxy}-3-methyl-4-oxo-2-phenyl-4H
-1-benzopyran;
8-{5-[4-(2-methoxyphenyl)-1-piperazinyl]-pentoxy}-3-methyl-4-oxo-2-phenyl-4
H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-oxo-1-piperazinyl]-propoxy}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{2-[2-(2,6-dimethoxyphenoxy)-ethylamino]-ethoxy}-3-methyl-4-oxo-2-phenyl-
4H-1-benzopyran;
8-{2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxy}-3-methyl-4-oxo-
2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylthio}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylsulfonyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulfamyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylsulfamyl}-3-methyl-4-
oxo-2-phenyl-4H-1-benzopyran;
8-{N-aminocarbonyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamino}-3-meth
yl-4-oxo-2-phenyl-4H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-oxobutyl}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran;
8-{3-[2-(1,4-benzodioxanyl)methylamino]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl}-3-methyl-4-oxo-2-phenyl-4H-1
-benzopyran;
8-[3-(4-phenyl-1-piperidinyl)propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-
benzopyran;
8-[3-(4,4-Diphenyl-1-piperidinyl)propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4
H-1-benzopyran;
8-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-{3-[4-(2-oxo-1-benzimidazolinyl)-1-piperidinyl]propyl-carbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-pyrimidinyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
8-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylsulfamyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{3-[N-methyl-2-(2-methoxyphenoxy)-ethylamino]propylcarbamoyl}-3-methyl-4-
oxo-2-phenyl-4H-1-benzopyran;
8-{N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]propionamido}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-phenyl-4-oxo-4H-
1-benzopyran;
8-{3-[2-(3,4-dihydro-1,
(2H)-naphthalenonyl)methylamino]propylcarbamoyl}-3-methyl-4-oxo-2-phenyl-4
H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethoxycarbonylmethyl}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butylsulfamyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
8-{N,
2-tetrahydropyranyloxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamo
yl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butyramido}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran;
E-8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethoxyiminomethyl}-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran;
8-{N-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran;
E-8-{2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylcarbamoyl]ethenyl}-3-met
hyl-4-oxo-2-phenyl-4H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butylsulfinyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
8-{3-[3-(2-methoxyphenoxy)propylamino]propylcarbamoyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
3-methyl-8-{3-[2-(2-methylthiophenoxy)ethylamino]propyl
carbamoyl}-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[2-(2,6-dimethoxyphenoxy)ethylamino]propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
(E)-8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-1-butenyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
(E)-8-{2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethoxycarbonyl]ethenyl}-3-me
thyl-4-oxo-2-phenyl-4H-1-benzopyran;
8-{{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylcarbamoyl}methyl}-4-oxo-2-phe
nyl-4H-1-benzopyran;
8-{N-acetyl-N,3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylsulfonylamino}-3-methyl-4-oxo-
2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthiocarbamoyl}-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran;
8-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butylsulfonyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran;
3-hydroxymethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-
oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-phenyl-4H-
1-benzopyran;
2,3-dihydro-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-
4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-4H-1-benzopy
ran;
6-bromo-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4
-oxo-2-phenyl-4H-1-benzopyran;
6-methoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
6-hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
3,6-dimethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo
-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-6-nitro-4
-oxo-2-phenyl-4H-1-benzopyran;
6-amino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4
-oxo-2-phenyl-4H-1-benzopyran;
6-acetylamino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-2-phenyl-4H-1-benzopyran;
6-ethylamino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-2-phenyl-4H-1-benzopyran;
6-dimethylamino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-
methyl-4-oxo-2-phenyl-4H-1-benzopyran;
7-methoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
4-trifluoromethylphenyl)-4H-1-benzopyran;
2-(4-benzoylphenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl
}-3-methyl-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
4-phenoxyphenyl)-4H-1-benzopyran;
2.
3-dimethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-ox
o-4H-1-benzopyran;
2-tert-butyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-4H-1-benzopyran;
2-cyclohexyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-4H-1-benzopyran;
2-(2-furyl)-8-{3-[4-(2-methoxylphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-t
hienyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-phenyl-4H-
1-benzothiopyran;
(E)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo
-2-(2-phenylethenyl)-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(4-meth
ylphenyl)-4-oxo-4H-1-benzopyran;
2-(4-methoxyphenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl
}-3-methyl-4-oxo-4H-1-benzopyran;
2-(4-fluorophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl
carbamoyl}-3-methyl-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-6-methan
esulfonylamino-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(4-nitr
ophenyl)-4-oxo-4H-1-benzopyran;
6-diethoxyphosphonyloxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarba
moyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-t
rifluoromethyl-4H-1-benzopyran;
8-{N,3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl-N-methylcarbamoyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran;
2-benzoyl-3-ethyl-7-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propcarbamoyl}ben
zo[b]furan;
2-(4-biphenylyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3
-methyl-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
3-pyridyl)-4H-1-benzopyran;
8-{3-[4-(2-acetoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran;
3-methyl-8-{3-[4-(2-methylaminocarbonyloxyphenyl)-1-piperazinyl]propylcarba
moyl}-4-oxo-2-phenyl-4H-1-benzopyran;
6-acetoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
(R,S)-2,3-dihydro-4-hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylc
arbamoyl}-4H-1-benzopyran;
2-(4-aminophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-
3-methyl-4-oxo-4H-1-benzopyran;
2-(4-acetylaminophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarb
amoyl}-3-methyl-4H-1-benzopyran;
2-(4-hydroxyphenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoy
l}-3-methyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-2-phenyl-4,
N.sub.1, N4-trioxo-4H-1-benzothiopyran;
7-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenylbenzo[b]fu
ran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl-N-methylsulfamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]butyl-N-methylsulphamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
2-(4-dimethylaminophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcar
bamoyl}-3-methyl-4-oxo-4H-1-benzopyran;
3-benzyloxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-
2-phenyl-4H-1-benzopyran;
8-{3-[4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[2-(8-methoxy-1,4-benzodioxanyl)methylamino]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenyl-4-thioxo-
4H-1-benzopyran;
8-{[2,2-dimethyl-3-(4-(2-methoxyphenyl)-1-piperazinyl)propyl]-carbamoyl}-3-
methyl-4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
2-phenylethyl)-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenyl-1,1,4-tri
oxo-4H-1-benzothiopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran-N.sub.1 -oxide;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran N.sub.1, N.sub.4 -dioxide;
8-{3-[4-(5-fluoro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenyl-4(1H)-qui
nolone;
2-(4-cyanophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-
3-methyl-4-oxo-4H-1-benzopyran;
6-cyano-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4
-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(4-fluoro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-(3-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{3-[4-(4-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
3-methoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-
phenyl-4H-1-benzopyran;
3-Hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-
phenyl-4H-1-benzopyran;
2-Cyclohexyl-3,4-dihydro-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarb
amoyl}-2H-1-benzopyran;
2-benzyl-3-ethyl-7-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}be
nzo[b]furan;
8-{3-[4-(2-isopropoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-
2-phenyl-4H-1-benzopyran;
8-{[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-methyl}3-methyl-4
-oxo-2-phenyl-4H-1-benzopyran;
8-{3-[4-[5-(1,4-benzodioxanyl)]-1-piperazinyl]propylcarbamoyl}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran;
3-ethoxymethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-o
xo-2-phenyl-4H-1-benzopyran;
8-{[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamino]methyl}-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran;
7-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-(4-nitrophenyl)i
ndole;
8-{3-[4-(5-hydroxy-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran;
3-ethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenoxy)-1-piperidinyl]propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran;
8-{3-[4-(2,3-dihydrobenzo[b]furan-7-yl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-2-phenyl-4H-1-benzopyran;
2-(2-biphenylyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3
-methyl-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(1-naph
thyl)-4-oxo-4H-1-benzopyran;
3-benzyloxymethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-
2-phenyl-4H-1-benzopyran;
3-methyl-8-{3-[4-[2-[(4-morpholinylmethyl)benzoyloxy]phenyl]-1-piperazinyl]
propylcarbamoyl}-4-oxo-2-phenyl-4H-1-benzopyran;
8-{2-[4-(2-methoxyphenyl)-1-piperazinyl}ethoxycarbonylamino]-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-3-methyl-2-(3-nitr
ophenyl)-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-(1,4-diazepinyl)]propylcarbamoyl}-3-methyl-4-ox
o-2-phenyl-4H-1-benzopyran;
2-cyclohexyl-3,4-dihydro-4-hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]
propylcarbamoyl}-2H-1-benzopyran;
3,4-dihydro-4-hydroxy-8-{3-[4-(2-methoxyphenyl)1-piperazinyl]propylcarbamoy
l}-2-phenyl-2H-1-benzopyran;
2-(1-adamantyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-
methyl-4-oxo-4H-1-benzopyran;
8-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentylsulfonyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
3,4,5-triiodophenyl)-4H-1-benzopyran;
2-cyclopropyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-4H-1-benzopyran;
8-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl}-3-methyl-4-oxo-2-phenyl-4H-
1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(4-meth
ylcyclohexyl)-4-oxo-4H-1-benzopyran;
2-cyclopentyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(1-phen
ylcyclopentyl)-4-oxo-4H-1-benzopyran;
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(1-meth
ylcyclohexyl)-4-oxo-4H-1-benzopyran;
2-(bicyclo[2.2.1]hept-5-en-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]pr
opylcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran, mixture of endo-exo
isomers;
2-(bicyclo[2.2.1]hept-5-en-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]pr
opylcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran, endo isomer;
2-(bicyclo[2.2.1]hept-5-en-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]pr
opylcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran, exo isomer;
2-(bicyclo[2.2.1]heptan-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propy
lcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran, mixture of endo-exo
isomers;
2-(bicyclo[2.2.1]heptan-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propy
lcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran, exo isomer;
2-cycloheptyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-m
ethyl-4-oxo-4H-1-benzopyran;
8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-1-methyl-2-phenyl-
1,2,3,4-tetrahydroquinoline;
(trans)-2-(4-methoxycyclohexyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]pro
pylcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran;
(cis)-2-(4-methoxycyclohexyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propy
lcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran;
8-{3-[4-(7-benzofuranyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{3-[4-(2-chlorophenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran;
8-{3-[4-(4-chlorophenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran; or a pharmaceutically acceptable salt
thereof.
13. A pharmaceutical composition comprising the compound of claim 1
or pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable diluent or carrier.
14. A pharmaceutical composition comprising the compound of claim
12 or an enantiomer, a diastereomer, an N-oxide, a prodrug, a
metabolite, a prodrug of a metabolite, or a pharmaceutically
acceptable salt of said compound and a pharmaceutically acceptable
diluent or carrier.
15. A compound according to claim 1, having .alpha.1 adrenergic
activity.
16. A compound according to claim 1, having 5-HT.sub.1A
serotonergic activity.
17. A compound according to claim 1 wherein B is ##STR30## wherein
n is 1 or 2, and A represents a phenyl group; wherein said phenyl
group is unsubstituted or substituted by one or more substituents
selected from the group consisting of alkoxy, alkyl, halogen, and
hydroxy, or A represents a 2-pyrimidinyl group or a bicyclic ring
of formula ##STR31## where ---- represents a single or double bond
and E represents an oxygen atom or a bond.
18. A compound according to claim 1 wherein B is ##STR32## wherein
L represents one or two groups selected among phenyl,
4-fluorobenzoyl or a 2-oxo-1-benzimidozolinyl group or a group of
the formula (CH.sub.2).sub.n -O-A wherein n=0, 1, or 2.
19. A compound according to claim 1 wherein B is ##STR33## and each
of R.sub.10 and R.sub.11 independently represents a hydrogen atom
or an alkoxy or alkylthio group, R.sub.12 represents a hydrogen
atom or an alkyl group and n is 2 or 3.
20. A compound according to claim 1 wherein B is ##STR34## and
R.sub.13 represents a hydrogen atom or a alkoxy group.
21. A compound according to claim 1 wherein B is ##STR35##
22. A compound according to claim 1 which is selected from the
group consisting of:
8-[3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-2-cyclohe
xyl-3-methyl-4-oxo-4H-1-benzopyran;
2-(4-chlorophenyl)-8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]
-3-methyl-4-oxo-4H-1-benzopyran;
2-(4-ethylaminophenyl)-8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbam
oyl]-3-methyl-4-oxo-4H-1-benzopyran;
2-(4-methansulfonylaminophenyl)-8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]pro
pylcarbamoyl]-3-methyl-4-oxo-4H-1-benzopyran;
8-[3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-2-(4-chlo
rophenyl)-3-methyl-4-oxo-4H-1-benzopyran;
2-(t-butyl)-7-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]benzofu
ran;
2-(t-butyl)-7-[3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoy
l]benzofuran;
8-[3-[4-[5-chloro-2-(1-methylethoxy)phenyl)-1-piperazinyl]propylcarbamoyl]-
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran;
8-[3-[4-(5-chloro-2-hydroxyphenyl)-1-piperazinyl]propylcarbamoyl]-3-methyl-
4-oxo-2-phenyl-4-1-benzopyran;
8-[3-[4-(2,5-dimethoxyphenyl)-1-piperazinyl]propylcarbamoyl]-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran;
8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-3-methyl-4-oxo-2-p
entafluoroethyl-4H-1-benzopyran; and
(cis)-2-(4-hydroxycyclohexyl)-8-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propy
lcarbamoyl]-3-methyl-4-oxo-4H-1-benzopyran.
23. A compound according to claim 3, wherein ---- represents a
double bond, W represents a carbonyl group, X represents an oxygen
atom, Y represents --CONH--, Z is propyl, B is B1, n is 1, R.sub.2
represents a phenyl group or a cycloalkyl group, R.sub.3 represents
a methyl group, R.sub.6 represents a hydrogen atom, R.sub.7
represents a hydrogen atom and A is a phenyl group substituted with
a methoxy group and optionally a halogen.
24. A compound according to claim 23, which is selected from the
group consisting of:
8-{3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran;
2-cyclohexyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-4H-1-benzopyran; and
8-[3-[4-(5-chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-2-cyclohe
xyl-3-methyl-4-oxo-4H-1-benzopyran.
Description
BACKGROUND OF THE INVENTION
Flavoxate, which is
8-(2-piperidinoethoxycarbonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,
and has the formula ##STR1## is used as a pharmaceutical agent for
urinary tract disturbances as it possesses a smooth muscle relaxing
activity attributable to its calcium antagonist activity. This
activity is exerted on the bladder dome smooth muscles or can be
related to an effect on the micturition center in the central
nervous system.
The compounds of the invention, described below, essentially
include more complex amino moieties in place of the piperidine
group. Further changes include alternatives to the ethoxycarbonyl
group which links the amino moiety to the benzopyran ring,
alternative 2-, 3-, 6- and 7-substitution patterns in the
benzopyran ring, replacement of the ring heteroatom by a sulfur
atom or by a sulfinyl or sulfonyl group, or by a nitrogen atom or
an amino group, and/or 2,3-hydrogenation of the benzopyran ring.
Further variations of the heterocyclic ring, are described below.
These structural variations give the new compounds the ability to
interact with different biological systems, as supported by the
affinity of the new compounds for the .alpha..sub.1 -adrenergic and
5HT.sub.1A -serotoninergic receptors. Flavoxate is practically
devoid of affinity for these receptors.
SUMMARY OF THE INVENTION
In one aspect, the invention is directed to compounds of Formula I:
##STR2## wherein ---- represents a single or double bond;
X represents a nitrogen, oxygen or sulfur atom, or an amino or
alkylamino group, a sulfinyl or sulfonyl group;
W represents a carbonyl, thiocarbonyl, hydroxymethylene, or a
methylene group or a bond;
when X is nitrogen and W is a methylene, the fused rings represent
a quinoline; when X=NH and W=CO, the tautomer X=N and W=C(OH) is
also considered to be included in the foregoing Formula I);
R.sub.2 represents a hydrogen atom or an alkyl, alkenyl, alkynyl,
carbocyclic or heterocyclic group, each of which groups may
optionally be substituted by one or more substituents selected from
the group consisting of alkyl, cyano, hydroxy, alkoxy, halogen,
phenyl, phenoxy, trifluoromethyl, nitro, amino, acylamino,
alkylamino, dialkylamino, alkylsulfonylamino and benzoyl; or
R.sub.2 itself represents a trifluoromethyl or an aroyl group;
R.sub.3 represents a hydrogen atom or an alkyl, hydroxyalkyl,
alkyl-O--R.sub.4 phenyl, hydroxy, or O--R.sub.4, wherein R.sub.4
represents an alkyl group optionally substituted with an aryl
group;
R.sub.6 represents a hydrogen or halogen atom or a nitro, amino,
acylamino, alkylsulfonylamino, alkylamino, dialkylamino, cyano,
hydroxy, alkoxy or alkyl group;
R.sub.7 represents a hydrogen atom or an alkoxy group;
Y represents one of the following groups, each of which is depicted
with its left hand end being the end which attaches to the
heterobicyclic ring and its right hand end being the end which
attaches to the group Z: ##STR3## Z represents a linear or branched
chain alkylene group having from 1 to 6 carbon atoms and optionally
having one hydroxy substituent; and
B represents one of the following groups: ##STR4## wherein n is 1
or 2 and A represents a phenyl group substituted by one or more
substituents (preferably at position 2) selected from the group
consisting of alkoxy, alkyl, halogen, hydroxy, or A represents a
2-pyrimidinyl group or a bicyclic ring of formula ##STR5## where
--- represents a single or double bond and E represents an oxygen
atom or a bond; ##STR6## wherein L represents one or two groups
selected among phenyl, 4-fluorobenzoyl or a
2-oxo-1-benzimidazolinyl group or a group of the formula
(CH.sub.2).sub.n --O--A wherein n=0, 1, or 2 and A has the same
meaning defined under B1; ##STR7## wherein each of R.sub.10 and
R.sub.11 independently represents a hydrogen atom or an alkoxy or
alkylthio group, R.sub.12 represents a hydrogen atom or an alkyl
group and n is 2 or 3, ##STR8## wherein R.sub.12 has the meaning
defined under B3 and R.sub.13 represents a hydrogen atom or an
alkoxy group; and ##STR9## wherein R.sub.12 has the meaning defined
under B3.
The invention further includes prodrugs of the formula I compounds,
e.g., the derivatives of compounds of formula I bearing reactive
groups such as NH, NH.sub.2 and in particular OH (i.e., at
positions W, R.sub.2, R.sub.3, R.sub.6, Z, B.sub.1, B.sub.2)
prepared for various purposes, e.g., to improve the
pharmaco-kinetic properties (adsorption, distribution, metabolism,
plasmatic half-life, etc.) of said compounds of formula I, which
can be administered in this "masked" or prodrug form and are
liberated, exerting their pharmacological action, in mammals
receiving them. Examples of these prodrug derivatives have the
following structure
wherein
J is a bond, an oxygen or sulfur atom, or a NH group,
F represents an alkyl group (optionally containing hetero atoms
such as O, S, N or substituted nitrogen), a carbocyclic group or
heterocyclic group, optionally substituted with amino, alkylamino,
dialkylamino, dialkylaminoalkyl, carboxy, alkoxycarbonyl,
carboxamido.
Preferably, J is a bond and F is CH.sub.3, (CH.sub.3).sub.3 C,
CH.sub.3 (CH.sub.2).sub.3, B'-CH.sub.2 -phenyl, B'-alkyl,
B'-CO-alkyl, HOCO-alkyl, alkyl-OCO-alkyl, where B' represents a
dialkylamino group or a cyclic amino group, optionally containing
other heteroatoms such as N, O or S.
Also included in the invention are derivatives having the
formula:
Other examples of prodrug derivatives are those obtained by the
derivatization of "acidic" NH groups (Ny) such as those present in
Y3, Y10, Y14, Y19, Y22, Y27, Y33, Y36 and Y41, yielding derivatives
having the formula:
wherein Z represents hydrogen atom or alkyl, phenyl or
trichloromethyl group and J and F have the same meaning and
preferred meaning as described above.
Additional prodrug examples are derivatives of the formula:
wherein B' has the same meaning as above.
The invention also includes the enantiomers, diastereoisomers,
N-oxides and pharmaceutically acceptable salts of these compounds,
as well as metabolites of these compounds having the same type of
activity (hereafter sometimes referred to as "active metabolites"
and prodrugs of said "active metabolites").
The invention further provides pharmaceutical compositions
comprising a compound of Formula I or a prodrug, a metabolite, an
enantiomer, diastereoisomer, N-oxide or pharmaceutically acceptable
salt of such a compound or prodrug, in admixture with a
pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention is directed to methods for
preventing contractions (including noradrenaline-related
contractions) of the urethra and lower urinary tract, selectively
preventing said contractions (without substantially affecting blood
pressure), lowering blood pressure, and preventing potassium ion
induced contractions of the bladder, all by administering one or
more selected compounds of the Formula I to a mammal (including a
human) in need of such treatment in an amount or amounts effective
for the particular use.
In yet another aspect, the invention is directed to methods for
blocking .alpha.1 and/or 5-HT.sub.1A receptors, by delivering to
the environment of said receptors, e.g., to the extracellular
medium (or by administering to a mammal possessing said receptors)
an effective amount of a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, and literature references cited
in this application are incorporated by reference in their
entirety.
The adrenergic antagonistic activity of compounds of the invention
renders them useful as agents acting on body tissues particularly
rich in .alpha..sub.1 -adrenergic receptors (such as blood vessels,
prostate, urethra, etc.). Accordingly, anti-adrenergic compounds
within the invention established as such on the basis of their
receptor binding profile, can be useful therapeutic agents for the
treatment, for example, of hypertension and of micturition problems
associated with obstructive disorders of the lower urinary tract,
including but not limited to benign prostatic hypertrophy
(BPH).
The serotonergic activity of compounds within the present invention
renders them useful as agents acting on tissues, particularly in
the central nervous system, where 5HT.sub.1A receptors are
functioning. 5HT.sub.1A receptors are believed to regulate the
action and release of serotonin as well as the release of other
neuromediators and are found both pre- and post-synaptically. The
compounds of the invention have biological activity in blocking
binding between these receptors and their various specific ligands
(e.g., serotonin). Accordingly, the compounds of the invention that
interact with the 5HT.sub.1A receptor (established as such on the
basis of their receptor-binding profile) are useful for the
treatment of anxiety disorders and depression.
Surprisingly, compounds within the invention (especially those
displaying affinity for both the .alpha..sub.1 -adrenergic and the
5HT.sub.1A serotoninergic receptors) show high selectivity for the
mammalian lower urinary tract, i.e., they are substantially more
active in antagonizing urethral contractions than in lowering blood
pressure. On the contrary, known .alpha.1-antagonists, such as
prazosin(1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)piperazine;
GB 1,156,973) do not exhibit such selectivity (and in fact cause
hypotension as a most common side-effect) while flavone derivatives
structurally similar to flavoxate, such as terflavoxate
(1,1-dimethyl-2-(1-piperidinyl)ethyl
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate
hydrochloride; EP 72 620) have no effect on urethral contractions.
(Naturally, those compounds of the invention that are not selective
for the lower urinary tract are preferred as antihypertensive
agents, but even the selective compounds can often be used as
antihypertensives because of their low toxicity.)
Compounds within the invention have also shown a good antagonist
effect against contractions of rat bladder strip induced by
potassium chloride. This effect can be attributed to a calcium
antagonistic activity, which renders the new compounds useful as
spasmolytics of the lower urinary tract (i.e., useful in the
treatment of urinary incontinence, urge syndrome and other similar
disorders).
The majority of the compounds of the invention exhibit low
toxicity. Thus, they can be used in higher amounts, an advantage
that often more than compensates for a relatively lower level of
activity that some of these compounds have. Naturally, those
compounds exhibiting both high activity and low toxicity are
preferred.
The affinity of compounds of the invention for each receptor can be
assessed by receptor binding assays, for example as follows:
(1) .alpha..sub.1 --adrenergic receptor: using the specific ligand
.sup.3 H-prazosin, according to Morrow, A. L. et al., Eur. J.
Pharmacol. 109: 285, 1985;
(2) 5HT.sub.1A --serotonergic receptors using the specific ligand
.sup.3 H-8-0H-DPAT according to Hoyer, D. et al., Eur. J.
Pharmacol., 118: 13, 1985.
It should be noted that identification and characterization of the
foregoing receptors is still in progress and that their types and
especially subtypes are subject to review and refinement. See,
e.g., Perez, D. M., et al Mol. Pharmacol., 40:876, 1991;
Garcia-Sainz, J. A., et al, Biochem. Biophys. Res. Comm.,
186(2):760, 1992; Zifa, E., et al., Pharmacol. Rev., 44(3):401,
1992; Hartig, P. R., et al., Drug Delivery Res., 26(3), 215, 1992;
Romero, A. G., et al., Annual Reports in Medicinal Chemistry,
27(3), 21, 1992, Academic Press.
The group ##STR10## will be abbreviated hereinafter as Fl. The
alphanumerics Y1 through Y49 and B1 through B5 will be used as
abbreviations for the groups Y and B above to which they
respectively apply.
Without limitation, alkyl groups within the definition of R.sub.2
include C.sub.1 -C.sub.6 alkyl; alkenyl groups include C.sub.2
-C.sub.4 alkenyl; carbocyclic groups include cyclohexyl and aryl
and heterocyclic groups include rings having one or two heteroatoms
and 4 or 5 carbon atoms, such as thienyl, furyl, pyridinyl.
Without limitation, alkyl groups, as well as the alkyl moiety of
other groups within the definition of R.sub.2, R.sub.3, R.sub.6,
R.sub.7, B.sub.1, R.sub.10, R.sub.11, R.sub.12 and R.sub.13,
include C.sub.1 -C.sub.4 alkyl.
The preferred values of the substituents in the group Fl are (most
preferably simultaneously) as follows:
______________________________________ : a double bond, X: an
oxygen atom, W: a carbonyl group, R.sub.2 : a phenyl group, R.sub.3
: a methyl group, R.sub.6 : a hydrogen atom, and R.sub.7 : a
hydrogen atom. ______________________________________
The group having all these preferred substituents, that is the
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-yl group, will be
abbreviated hereinafter as Fl'.
The preferred (most preferably simultaneously with Fl') groups
which Z may represent are trimethylene and tetramethylene. Y
preferably represents one of the groups Y2, Y3, Y37, Y40, Y41 or
Y42. B preferably represents one of the groups B1 or B3, especially
the group 1-(2-methoxyphenyl)piperazinyl.
SYNTHESIS OF THE COMPOUNDS OF THE INVENTION
The compounds according to the invention may generally be prepared
(except when the groups R6 and the substituents at R.sub.2 are OH,
NH.sub.2 or aminoalkyl and Y=Y15 or Y29) as follows:
Path a:
By condensing compounds Fl-Y-Z-L, wherein L represents a halogen
atom or a leaving group such as a tosylate group, with a compound
H-B. The condensation is preferably, but not necessarily, carried
out at a temperature within the range of 20.degree.-140.degree. C.
in a polar solvent such as dimethylformamide or methanol, or
without solvent, usually in the presence of a base such as
potassium carbonate. Such condensations are illustrated in Examples
1 to 3, 7 to 9, 11, 13 to 16, 21, 23 to 31, 38 to 42, 46 to 49, 54
to 59, 69, 73, 77, 78, 84, 133, 141, 145-147, 152, 154, 158, 160,
161, 168, 172, 187, 189 and 190 below. See, also Gibson's chapter
in Patai "The Chemistry of the Amino Group", p. 45 et seq. Wiley
Interscience, New York, 1968.
An alternative method for the preparation of the present compounds
is condensation (under the same conditions described in the
preceding paragraph) of a compound Fl-Y-H with a compound L-Z-B
wherein L is as above defined. This condensation is illustrated in
Examples 5, 6, 66, 79 and 81 below. By this route, compounds having
Y=Y15 or Y29 can also be prepared (see Gibson's chapter in Patai,
supra).
Compounds of formula (I) bearing a NH.sub.2 group in R.sub.6 or as
substituent in R2, may be prepared by reduction of the
corresponding compounds (I) wherein R6 or the substituent in R2 are
NO.sub.2 groups.
Such reduction can be carried out:
with Ni-Raney catalyst in aprotic solvent selected from methanol,
ethanol, isopropanol, water and mixtures of them; or
with SnCl.sub.2, H.sub.2 O, optionally in presence of hydrochloric
acid, either in aprotic solvent such as methanol, ethanol,
isopropanol, water, acetic acid and mixtures of them, or in an
aprotic solvent such as ethyl acetate; or
with Fe and aqueous hydrochloric acid in aprotic solvent such as
methanol, ethanol, isopropanol, water and mixtures of them.
The temperatures of the above reactions will be chosen in a range
between 20.degree. C. and 100.degree. C. (J. March, Advanced
Organic Chemistry, IV Ed., page 1216, Wiley Interscience, 1992).
Examples of this reduction are given in Examples 94 and 124.
Compounds of formula (I) having a NHAlk group as a R.sub.6
substituent can be prepared by monoalkylation, starting from the
corresponding parent compounds (I) where R.sub.6 =NH.sub.2. For
example, this may be done by first reacting the amino compound (I)
with an excess of trifluoroacetic anhydride, then reacting the
obtained trifluoroacetyl derivative with an alkyl-L reagent and
finally deprotecting the thus-obtained trifluoroacetyl-alkylated
derivative by treatment with K.sub.2 CO.sub.3 in methanol or with
sodium borohydride in methanol or dimethylsulfoxide.
These reactions are described in Examples 32 and 33, where they
were carried out on Y groups.
Alternatively, compounds of formula I having a NHAlk or
N(Alk).sub.2 groups as a R.sub.6 substituent or as a substituent on
the phenyl group in R.sub.2 can be obtained by alkylation of the
corresponding parent compounds (I) where R.sub.6 =NH.sub.2 with the
appropriate aldehydes in the presence of a reducing agent, such as
sodium cyanobrohydride. Descriptions of these reactions are given
in Examples 96, 97 and 131 below.
Compounds bearing a OH group as R.sub.6 or as a substituent in
R.sub.2 may be prepared starting from the corresponding parent
compounds (I) alkoxy-substituted at said positions. This can be
accomplished by treating the parent compounds, for example, with
BBr.sub.3 in dichloromethane at 0.degree.-40.degree. C. (T. W.
Greene "Protective Groups in Organic Synthesis", page 87, Wiley
Interscience (1981)) or according to other methods described in the
same reference.
Compounds of formula (I) having a saturated 2-3 bond
(----=.sub.--------) can be alternatively obtained:
by selective hydrogenation of the corresponding compounds of
formula (I) having a 2-3 double bond (----= );
by conversion of the appropriate intermediates with a saturated 2-3
bond which, in turn, can be obtained according to Schemes 4, 6-9,
11, 12 and 14 in the Starting Materials section.
These last conversions are performed according to the methods
described for compounds of formula (I) having a 2-3 double bond, in
particular when a nitro group is already present in the molecule.
This conversion is illustrated in Example 87.
The selective hydrogenations can be carried out using
alternatively:
hydrogen in presence of a metal or metal oxide catalyst (e.g.:
palladium on charcoal, or platinum dioxide) in a protic solvent at
20.degree.-120.degree. C. (E. H. Rodd, Chemistry of Carbon
Compounds, Vol. IVB, page 903, Elsevier, 1959). This hydrogenation
is described in Example 170. [Also, in this Example W=CO was
transformed into W=CHOH and R.sub.2 =phenyl was transformed into
R.sub.2 =cyclohexyl (Example 169).]
di-(isobutyl)aluminum hydride in an aprotic solvent (e.g.:
tetrahydrofuran and/or methylene chloride) at -70.degree./0.degree.
C. (R. Sarges et al., J. Med. Chem. 33, 1859 (1990).
Compounds of formula I having W=CHOH and a 2-3 single bond
(----=.sub.--------) can be obtained by reduction of the
corresponding parent compounds of formula I having W=CO and ----= ,
with sodium borohydride, as reported in Example 123 below.
In some cases, compounds of the Formula I may be prepared by
conversion of other (parent) compounds of the invention. Such
conversions include:
Path b:
Fl-CO-Z-B to Fl-CH(OH)-Z-B by reduction as illustrated in Examples
17 to 20 below,
Path c:
Fl-CH(OH)-Z-B to Fl-(CHOAlkyl)-Z-B by etherification as illustrated
in Example 22,
Path d:
Fl-(CH.sub.2)n-NH-Z-B.fwdarw.Fl-(CH.sub.2)n-NCH.sub.3 -Z-B where
n=0, 1, by methylation as illustrated in Example 35;
Path e:
Fl-(CH.sub.2)n-NH-Z-B.fwdarw.Fl-(CH.sub.2)n-N(COCH.sub.3)-Z-B where
n=0, 1, by N-acetylation as illustrated in Example 36;
Path f:
Fl-(CH.sub.2)n-NH-Z-B.fwdarw.Fl-(CH.sub.2)n-N(CONH.sub.2)-Z-B where
n=0, 1, by reaction with potassium isocyanate as illustrated in
Example 50;
Path g:
Fl-CH(OH)-Z-B.fwdarw.Fl-CO-Z-B by oxidation, as illustrated in
Example 51;
Path h:
Fl-Y-Z-B.fwdarw.Fl-Y-Z-B(N-oxide) by oxidation as illustrated in
Example 43, 127, 139 and 140.
Path i:
H.sub.2 N-Fl-Y-Z-B.fwdarw.CH.sub.3 CONH-Fl-Y-Z-B (where in H.sub.2
N-Fl represents a Fl group bearing an amino group as the R6 group
or as the substituent in R.sub.2) using the N-acylation method
described in Examples 36, 95 and 125.
Path j:
Fl (R6=NH.sub.2)-Y-Z-B.fwdarw.Fl(R6=CH.sub.3 SO.sub.2 NH)-Y-Z-B by
amidification using the method described in Example 112. ##STR11##
by N-alkylation using the procedure described in Examples 35 and
62.
Some compounds may be prepared by addition reactions. For example
those in which Z contains a hydroxy substituent may be prepared by
addition across an epoxy group ##STR12## as illustrated in Example
45.
Addition across a double bond is also possible, e.g.:
Path m:
Fl-Y-CH.dbd.CH.sub.2 +H-B.fwdarw.Fl-Y-CH.sub.2 -CH.sub.2 -B as
illustrated in Examples 37, 63 and 82.
Other synthetic schemes include the formation of Y, Z or B during
the reaction, for example.
Path n:
Fl-(X)-(Q)-Cl+A-HN-Z-B.fwdarw.Fl-(X)-(Q)-N(A)-Z-B (wherein X=bond,
CH.sub.2 or CH.dbd.CH, Q=CO or SO.sub.2, and A=H, alkyl or OP.sub.r
wherein P.sub.r is a protective group) as illustrated in Example 12
(particularly preferred) and in Examples 60, 61, 64, 67, 68, 72,
87, 88, 93, 98, 116, 129, 130, 135 and 136.
The same compounds may also be prepared by other routes
including:
Fl-(X)-COOH+A-NH-Z-B in presence of a coupling agent (e.g.,
dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or diethyl
cyanophosphonate) optionally in the presence of a promoting agent
(e.g., N-hydroxysuccinimide, 4-dimethylaminopyridine in an aprotic
or a chlorinated solvent (e.g., dimethylformamide, chloroform) at
-10.degree./140.degree. C. (Albertson, Org. React. 12, 205-218
(1962); Doherty et al., J. Med. Chem. 35:2 (1992); Staab et al.,
Newer Methods Prep. Org. Chem., 5: 61 (1968); Ishihara, Chem.
Pharm. Bull., 39, 3236 (1991)); as illustrated in Examples 80, 86,
89, 90, 92, 99-111, 113-115, 117-119, 128, 132, 137, 142-144,
148-151, 153-155, 157, 159, 162-164, 167, 171, 176-180 and 183-186.
In some cases the activated intermediate esters (such as
N-hydroxysuccinimidyl esters) can be isolated (see for example
Intermediate CXVII) and transformed into the corresponding amides
by reacting with A-NH-Z-B in aprotic or chlorinated solvent at
-10.degree./100.degree. C., as illustrated in Example 138.
Fl-(X)-COOH+A-NH-Z-B without a solvent at 150.degree.-220.degree.
C. (Mitchell et al., J. Am. Chem. Soc. 53: 1879 (1931) or in
high-boiling ethereal solvents (e.g., diglyme);
Fl-(X)-COO-Alk+A-NH-Z-B optionally in the presence of a coupling
agent (e.g.: trimethylaluminum) in an aprotic and/or a chlorinated
solvent (e.g., hexane, dichloromethane) at -10.degree./80.degree.
C., or without solvents at 80.degree.-180.degree. C., (S. M.
Weinreb et al., Tetrahedron Lett. , 1977, 4171); M. F. Lipton et
al., Org. Synth. 59:49 (1979));
Fl-(X)-COOH+alkyl chloroformate in presence of a tertiary amine
(e.g., triethylamine) followed by addition of A-NH-Z-B at
0.degree.-80.degree. C.; optionally a promoting agent (e.g.:
1-hydroxypiperidine) may be added before the amine addition
(Albertson, Org. React. 12: 157 (1962).
Path o:
Fl-COCl+HS-Z-B.fwdarw.Fl-Y49-Z-B.
Path p:
Fl-COCl+HO-Z-B.fwdarw.Fl-Y2-Z-B as illustrated in Example 10.
Path q:
FlCHO+H.sub.2 NO-Z-B.fwdarw.Fl-Y11-Z-B, as illustrated in Example
70.
Path r:
Fl--CHO+A-HN-Z-B.fwdarw.Fl-CS-N(A)-Z-B (where A=H; CH.sub.3) in
presence of sulfur in an aprotic solvent (e.g., dimethylformamide
or pyridine at 60.degree.-120.degree. C. (M. Carmack et al., Org.
Reaction 3: 83 (1947) and R. Benassi et al., Org. Magn. Res. 15, 25
(1981)), as illustrated in Example 83.
Path s:
Fl-NH.sub.2 +HCO-Z-B.fwdarw.Fl-Y29-Z-B as illustrated in Example
43, 127, 139 and 140.
Path t:
Fl-Y-CH.sub.3 +HO-CH.sub.2 -B.fwdarw.Fl-Y-CH.sub.2 -CH.sub.2 -B as
illustrated in Example 4,
Path u:
Fl-CH.dbd.CH--CONH.sub.2 +HOCH.sub.2 -B.fwdarw.Fl-Y10-CH.sub.2 -B.
##STR13## under reducing conditions as illustrated in Example 44.
##STR14## as illustrated in Examples 74, 75 and 76. ##STR15## as
illustrated in Example 52. ##STR16## as illustrated in Example 65.
Path y:
Fl-Y-Z--CHO+HB.fwdarw.Fl-Y-Z-B as illustrated in Example 53 and
175.
Path z:
Fl-COOH+HO-Z-B.fwdarw.Fl-Y48-Z-B, in the presence of
diphenylphosphorylazide and triethylamine in an aprotic solvent
(e.g. dioxane) at 60.degree.-100.degree. C. (T. Shioiri et al., J.
Am. Chem. So., 94, 6203 (1972)), as illustrated in Example 166.
Path aa:
Fl--CHO+AHN-Z-B.fwdarw.Fl-Y15 -Z-B or Fl-Y16 -Z-B, under conditions
of reductive amination as reported above and illustrated in Example
156.
Persons skilled in the art are aware that all the above synthetic
paths b) to y) might be simplified provided that the reacting
intermediate does not bear further groups sensitive to the same
reactants (for example: CO, NH.sub.2, NHAlk or OH groups).
Compounds of formula (I) bearing the above cited reactive groups
can be prepared through paths b) to y) on condition that the
reactive groups present in the starting materials are converted
into non-reactive groups before reacting and then deprotected at
the end of the reaction as illustrated in Example 71. Several
examples of protection and deprotection for various reactive groups
can be found in: T. W. Greene, "Protective Groups in Organic
Synthesis"--Wiley Interscience (1991).
Alternatively, unreactive groups (e.g., NO.sub.2) can be left
unconverted during the first reaction and then converted to
reactive ones (e.g.: NH.sub.2) as a final step of the pathway. See,
for example, path a).
Which synthetic technique will be preferred depends on the compound
desired to be synthesized, but path n) is generally preferred for
the compounds that can be made by it. Additional synthetic methods
will be apparent to those skilled in the art.
Starting Materials
Intermediates, such as the compounds Fl-Y-Z-L and Fl-Y-H used in
the preparation of compounds of the invention may themselves be
prepared from simple compounds such as Fl-COOH, Fl--CHO, Fl-COCl,
Fl-NH.sub.2 Fl-OH and FlCH.sub.2 CH.dbd.CH.sub.2 by transformations
known to those skilled in the art. Several such transformations are
described in detail in the Examples.
When X is oxygen and W is carbonyl group, many of the aforesaid
simple compounds are commercially available or their synthesis has
been published in the literature. Those which are not available may
be synthesized by cyclization according to the following Reaction
Scheme 1 wherein the steps have the various meanings described
below: ##STR17## Step 1a: Procedure without isolation of the
intermediate phenyl ester: R.sub.3 CH.sub.2 COCl or (R.sub.3
CH.sub.2 CO).sub.2 O and a Lewis acid (e.g., AlCl.sub.3 or
ZnCl.sub.2), without solvent or in aprotic solvent (e.g.,
nitrobenzene or chlorinated solvent) at 20.degree.-180.degree.
C.;
procedure with isolation of the intermediate phenyl ester: R.sub.3
CH.sub.2 COCl or (R.sub.3 CH.sub.2 CO).sub.2 O heated with the
starting material or other esterification methods, such as the
Schotten-Bauman procedure. The isolated ester is then heated in
nitrobenzene or other non protic solvent (e.g., chlorinated
solvent), or without any solvent, at 20.degree.-180.degree. C., in
the presence of a Lewis acid (e.g., AlCl.sub.3, or ZnCl.sub.2). (A.
M. Blatt, Org. React. 1: 342 (1942)).
Step 1b:
R.sub.2 COCl or (R.sub.2 CO).sub.2 O and R.sub.2 COONa alone or in
high-boiling non-protic solvent (e.g., o-dichlorobenzene) at
150.degree.-220.degree. C.; this reaction also allows for the
direct transformation of compounds 2 to 6, when compound 2 has
A=COOH;
R.sub.2 C(OAlk).sub.3 in the presence of HClO.sub.4 at
20.degree.-40.degree. C. or in pyridine as the reaction solvent in
the presence of piperidine at 60.degree.-80.degree. C.;
R.sub.2 COCl or (R.sub.2 CO).sub.2 O in a chlorinated solvent at
-10.degree./120.degree. C. in the presence of a base such as
1,8-diazabicycloundecene (DBU).
Step 1c:
R.sub.2 COCl in pyridine at 20.degree.-100.degree. C. or in
non-protic solvent at 0.degree.-80.degree. C., optionally in the
presence of a base, such as triethylamine or
4-dimethylaminopyridine.
Step 1d:
Potassium carbonate in acetone or methyl ethyl ketone at
20.degree.-80.degree. C.;
Sodium hydride in dimethylsulfoxide or tetrahydrofuran at
0.degree.-40.degree. C.;
Potassium hydroxide or potassium tert-butoxide in pyridine at
20.degree.-100.degree. C.
Step 1e:
Hydrochloric acid or sulfuric acid in acetic acid solvent at reflux
or an alcohol (methanol, ethanol, i-propanol) at 20.degree.
C.-reflux temperature;
Trifluoracetic acid in dichloromethane at 20.degree.-40.degree.
C;
p-toluenesulfonic acid in benzene or toluene at reflux.
Step 1f:
R.sub.2 COCl and potassium carbonate or potassium hydroxide in
water and a phase transfer catalyst in benzene or toluene at
reflux;
R.sub.2 COOAlk and lithium bis(trimethylsilyl)amide or lithium
diisopropylamide in tetrahydrofuran at -78.degree./0.degree. C.
Step 1g:
When A is a COOCH.sub.3 or COOC.sub.2 H.sub.5 group:
Sodium hydroxide in aqueous ethanol at 0.degree.-75.degree. C.;
Lithium hydroxide in aqueous dimethylformamide, methanol or
tetrahydrofuran or a mixture thereof at 10.degree.-100.degree.
C.;
Hydrochloric acid in aprotic solvent such as dioxane at
60.degree.-120.degree. C. When A is NO.sub.2 : Reduction with
Ni-Raney catalyst in aprotic solvent (e.g., i-propanol) or a
mixture of protic solvents at 20.degree.-100.degree. C.;
Reduction with hydrogen and a catalyst (e.g., Ni-Raney or
Palladium/C) in a protic solvent (e.g., methanol, ethanol,
i-propanol or mixtures thereof) at 20.degree.-100.degree. C.;
Reduction with SnCl.sub.2 in the presence of aqueous hydrochloric
acid in aprotic solvent (e.g., acetic acid) at
20.degree.-100.degree. C.;
Reduction in presence of Fe and aqueous hydrochloric acid in protic
solvent at 20.degree.-100.degree. C.
When A is a CH.dbd.CHCH.sub.3 group:
Oxidation with Na.sub.2 Cr.sub.2 O.sub.7 or other oxidizing agents
such as KMnO.sub.4 in acetone/sulfuric acid at
0.degree.-100.degree. C. The cyclization reaction reported in step
1b (or steps 1c, 1d and 1e) can also be carried out on Intermediate
2 of Scheme 1 where A is represented by Y.sub.3 -Z-B. The final
compounds of the invention corresponding to formula I can be
produced directly with this approach. It is illustrated in Examples
173 and 174.
When X represents a sulfur atom or a sulfinyl or a sulfonyl group
and W is carbonyl group, the simple starting materials may be
prepared according to the following Reaction Scheme 2 wherein the
steps have the following alternative meanings: ##STR18## Step 2a:
R.sub.2 COCH(R.sub.3)CN or R.sub.2 COCH(R.sub.3)COOAlk in
polyphosphoric acid at 50.degree.-120.degree. C.;
R2C.tbd.C-COOAlk and Al.sub.2 O.sub.3 in aprotic solvents (e.g.,
diethyl ether) at 0.degree.-40.degree. C.;
R.sub.2 C.tbd.C-COOAlk and a base in aprotic solvents (e.g.,
tetrahydrofuran or dimethylformamide) at 20.degree.-140.degree.
C.
The last two options are both followed by treatment with
polyphosphoric acid at 50.degree.-120.degree. C.
Step 2b:
Sodium hydroxide in aqueous ethanol at 40.degree.-75.degree. C.
Lithium hydroxide in aqueous dimethylformamide at
40.degree.-100.degree. C.
Step 2c:
Stoichiometric 30% hydrogen peroxide in acetic acid, at
25.degree.-60.degree. C.;
m-chloroperbenzoic acid in chloroform at 0.degree.-30.degree.
C.;
Step 2d:
30% hydrogen peroxide in acetic acid at 50.degree.-80.degree.
C.
The starting ortho-mercaptobenzoates are commercially available or
can be prepared by known methods: for example by transformation of
the corresponding orthoalkoxycarbonylbenzenediazonium salts upon
treatment with potassium ethylxanthate (M. S. Cohen et al., J. Org.
Chem. 18: 1380 (1953)).
Simple starting materials having R.sub.7 =OCH.sub.3, W=CO and X=O,
S may be prepared according to Reaction Scheme 3 wherein the step
3a is:
Step 3a:
Formaldehyde and gaseous HCl in acetic acid containing aqueous HCl
(d=1,18) at 50.degree.-100.degree. C. (P. Da Re et al., Ann. Chim.,
46:904 (1956)). This method can be used when R.sub.3 is different
from H or from a hydroxymethyl group. ##STR19##
Intermediates (1) can be prepared according to Reaction Schemes 1
and 2 starting from the appropriate phenols or thiophenols (not
substituted at position 2 or 6 with COOAlk or NO.sub.2); then, the
resulting Intermediates (2) can be converted using known methods to
starting materials suitable for obtaining the desired compounds of
the invention.
The synthesis of the simple 2,3-dihydro intermediates
(----=.sub.--------), provided that other reactive groups possibly
present (e.g., NH.sub.2, OH) have been previously protected as
described before, can be pursued using a method of the Reaction
Scheme 4, wherein the steps 4a-4i have the following meanings:
##STR20## Step 4a: R.sub.2 --CHO, aqueous sodium hydroxide in
ethanol or other protic solvent;
R.sub.2 --CHO, sodium hydride or potassium tert-butoxide in
tetrahydrofuran (or other dipolar aprotic solvent) at
0.degree.-150.degree. C.;
Step 4b:
Mineral acid (e.g., hydrochloric acid or sulfuric acid) in water or
other protic solvents (e.g., ethanol, acetic acid) at
0.degree.-100.degree. C.;
Step 4c:
R.sub.2 --CHO, 0.1-1N aqueous sodium hydroxide or other suitable
base in aprotic solvent;
R.sub.2 --CHO, pyrrolidine in aprotic (e.g., methanol) or polar
aprotic solvent at 0.degree.-100.degree. C. (H. J. Kabbe,
Synthesis, 1978, p.886);
Step 4d:
Lithium diisopropylamide in tetrahydrofuran at 0.degree.-20.degree.
C.; then trimethylsilylchloride and an organic base (e.g.,
triethylamine) (S. E. Kelly et al., J. Org. Chem. 56: 1325
(1991));
Step 4e:
R.sub.2 --CHO in a chlorinated solvent (e.g., CH.sub.2 Cl.sub.2) at
-78.degree. C. then TiCl.sub.4 (or other Lewis acid) (S. E. Kelly,
et al., J. Org. Chem., 56: 1325 (1991));
Step 4f:
Lithium diisopropylamide in tethrahydrofuran at -78.degree. C. then
R.sub.2 --CHO (A. Banerij et al., Tetrahedron Letter, 1979,
3685);
Step 4g:
R.sub.2 --CH.dbd.CR.sub.3 COCl, a Lewis acid (e.g., AlCl.sub.3) in
a suitable solvent (e.g., nitrobenzene) or without solvent at
20.degree.-180.degree. C.;
Step 4h:
R.sub.2 --CH.dbd.CR.sub.3 COOAlk, triethylbenzylammonium hydroxide
in an aprotic solvent (e.g.: benzene) or without solvent at
50.degree.-150.degree. C.; then aqueous NaOH in methanol at
20.degree.-50.degree. C. or lithium hydroxide in aqueous
dimethylformamide. (In this case compounds having A=COOCH.sub.3 or
COOC.sub.2 H.sub.5 are also hydrolyzed to compounds having
A=COOH);
Step 4i:
Concentrated sulfuric acid or phosphorus pentoxide or
polyphosphoric acid or a Lewis acid in nitrobenzene or toluene or
without solvent at 0.degree.-180.degree. C. (Also in this case,
hydrolysis of A=COOAlk to A=COOH occurs).
The Intermediates (4) thus obtained can be converted to the
corresponding derivatives having A=COOH or NH.sub.2 according to
the method of Scheme 1, step 1g. ##STR21##
Simple starting materials having R.sub.3 =OH or OR.sub.8, where
R.sub.8 is alkyl or arylalkyl, may be prepared according to
Reaction Scheme 5 where A has the same meaning as in Reaction
Scheme 1. Intermediates (1) and (2) (which are the same as (2) and
(3) in Reaction Scheme 4, but with R.sub.3 =H) can be prepared
according to Reaction Scheme 4 starting from the appropriate
phenols or thiophenols having R.sub.3 =H.
Steps 5a-5g have the following meanings:
Step 5a:
Aqueous sodium hydroxide in an alcoholic solvent (e.g., methanol or
ethanol) followed by 30% H.sub.2 O.sub.2 at -10.degree./-78.degree.
C. (N. D. Meyer et al., J. Med. Chem., 34,736, (1991) and
references cited therein) (not when A is CH.dbd.CH--CH.sub.3 ; when
A=COOR it is simultaneously transformed into COOH).
Step 5b:
(----=.sub.--------) Amylnitrite or other alkylnitrite without
solvent or in a suitable solvent (e.g., ethanol or benzene (in the
presence of a catalyst (e.g., 37% hydrochloric acid) (Org. React.,
7, 327 (1953)) and references cited therein), then aqueous sulfuric
acid in aprotic solvent (e.g., acetic acid) at
10.degree.-100.degree. C. (Acheson R. M., "An Introduction to the
Chemistry of Heterocyclic Compounds", 347 John Wiley end Sons, New
York, 1976).
(----= ) lithium diisopropylamide in dry tetrahydrofuran at
-78.degree. C.; then trimethylborate at -50.degree./-20.degree. C.;
then acetic acid and 30% hydrogen peroxide (B. D. M. Cunningham et
al., Anti-Cancer Drug Design, 7, 365 (1992).
Step 5c: Note: Intermediates (4) can be prepared by known methods
from the corresponding salycilates or thiosalycilates (see J.
March, "Advanced Organic Chemistry," 539, John Wiley and Sons, New
York, 1992; L. Rene et al., Eur. J. Med. Chem. - Chim. Ther., 12,
385, (1977) and references cited therein) R.sub.2
--CH.dbd.CH--NO.sub.2 (1-1,5 equivalent) in a suitable solvent
(e.g., diisobutylether, dimethylsulfoxide or dimethylformamide) in
the presence of a base (e.g., potassium or sodium hydroxide) in
catalytic or stoichiometric quantity at 20.degree.-150.degree. C.
(see L. Rene, above and T. Sakakibara et al., Bull. Chem. Soc. Jpn,
51, 3095, (1978)).
Step 5d:
H.sub.2 O.sub.2 15%, sodium hydroxide or other base (e.g.,
triethylamine) in a protic solvent (e.g., methanol) at
20.degree.-100.degree. C. (S. R. Deshpande et al., Synthesis, 835,
(1983)) or photolysis and alkaline hydrolysis (Rao T. S. et al.,
Heterocycles, 22, 1377, (1984), or KO.sub.2 in benzene containing
18-crown-6 ether at 20.degree.-100.degree. C. (Rao T. S.,
Heterocycles, 26, 2117, (1987)) (not when A is CH.dbd.CH--CH.sub.3
; when A=COOR it can be simultaneously transformed into COOH).
Step 5e:
R.sub.8 L, where L represents a leaving group (e.g., alkylsulphate,
halogen, rosylate) and a base (e.g., potassium carbonate, sodium
hydride, potassium or sodium or lithium hydroxide) in suitable
solvent (e.g., tetrahydrofuran, dimethylsulfoxide,
dimethylformamide, benzene) in the optional presence of a phase
transfer catalyst (e.g., benzyltriethylammonium bromide) at
0.degree.-180.degree. C.
Step 5f:
performed as described for step 1b of Reaction Scheme 1.
Intermediates (3) and (6) of Reaction Scheme 6 can be transformed
into the corresponding compounds having B (with the same meanings
as for Reaction Scheme 1) instead of A, according to the step
1g.
Simple starting materials having a thiocarbonyl instead of a
carbonyl group at position 4 of the heterocyclic ring may be
prepared according to Reaction Scheme 6, where A has the same
meaning as in Reaction Scheme 1. Intermediates (1) and (2) of this
scheme can be prepared according to Reaction Schemes 1, 2, 4 and
5.
Steps 6a-6d have the following meanings:
Step 6a:
P.sub.2 S.sub.5 in pyridine at 50.degree.-100.degree. C. (Stavaux
et al., Bull. Soc. Chim. Fr., 2082, (1967)).
Step 6b:
P.sub.2 S.sub.5 or B.sub.2 S.sub.3 or SiS.sub.2 or Lawesson's
reagent in a chlorinated solvent (e.g., chloroform) or in an
aromatic solvent (e.g., benzene, toluene, xylene) at reflux. (Dean
et al., J. Chem. Soc. C, 2192, (1963); R. K. Razdan et al., J. Med.
Chem., 21, 643, (1978); K, Clausen et al., Tetrahedron, 37, 3635
(1991)).
Step 6c:
COCl.sub.2 without solvent or with an inert solvent (e.g., benzene)
at 40.degree.-90.degree. C. (A. Schonberg et al., Chem. Ber., 101,
701, (1968)).
Step 6d:
Thioacetic or thiobenzoic acid or potassium diethylxantogenate in a
suitable solvent (e.g., benzene) at reflux (A. Schonberg, vide
supra).
Intermediates (4) of Reaction Scheme 7 can be transformed into the
corresponding compounds having B (with the same meanings as in
Reaction Scheme 1) instead of A, according to step 1g.
Simple starting materials with a CH.sub.2 or a CHOH group at the 4
position of the heterocyclic ring may be prepared according to
Reaction Scheme 7, where A has the same meanings as in Reaction
Scheme 1.
Intermediates (1), (2) and (4) can be prepared according to
Reaction Schemes 1, 2, 5 and 6.
Steps 7a-7h have the following meanings:
Step 7a:
1,2-Ethanedithiol or 1,3-propanedithiol in an aprotic solvent
(e.g., dichloromethane or benzene or toluene) at
0.degree.-110.degree. C. in the presence of a catalyst (e.g.,
p-toluenesulfonic acid or boron trifluoride etherate).
Step 7b:
R.sub.2 COCH.sub.2 R.sub.3 in a suitable mixture of solvents (e.g.,
ethyl acetate or dichloromethane plus ethanol or methanol)
saturated with gaseous hydrochloric acid at 0.degree.-40.degree.
C.; then aqueous perchloric acid in acetic acid at
20.degree.-100.degree. C. (L. Jurd, Tetrahedron, 28, 493,
(1972)).
Step 7c:
Lithium aluminum hydride in tetrahydrofuran at reflux (if A is
other than COOR and NO.sub.2);
Zinc iodide and sodium cyanoborohydride (6 equivalents) in a
chlorinated solvent (e.g., 1,2-dichloroethane) at room
temperature-reflux (C. K. Lau et al., J. Org. Chem., 51, 3038,
(1986)).
Step 7d:
Raney-Ni in an alcoholic solvent (e.g., isopropanol) at r.t. -
reflux (Hilton et al., J. Am. Chem. Soc., 90, 6887, (1968)).
Step 7e:
Sodium borohydride in a suitable solvent (e.g., methanol or ethanol
or dimethylsulfoxide) at -10.degree./50.degree. C. (L. Jurd, vide
supra);
Lithium aluminum hydride in tetrahydrofuran (or other suitable
solvent) at 0.degree.-50.degree. C. (when A is different from COOR
or NO.sub.2) (Degani et al., Ann. Chim., 61, 793, (1971); Kurosawa,
Bull. Chem. Soc. Jpn., 51, 1175, (1978)).
Step 7f:
Trityl perchlorate in acetonitrile at room temperature (Degani et
al., vide supra).
Step 7g:
Melting with P.sub.2 O.sub.5 at 80.degree.-180.degree. C. (Hortmann
et al., J. Am. Chem Soc., 96, 6118, (1974)).
Step 7h:
Sodium borohydride in ethanol or other suitable solvent at
0.degree. C. -reflux (K. Anaya, Bull. Chem. Soc. Jpn., 40, 1884,
(1967)).
Hydrogen (1-10 atm) in ethanol (or other suitable solvent) in the
presence of a catalyst such as Pd-C 5 or 10% or Raney-Ni or
PtO.sub.2 at r.t./80.degree. C. (K. Hanaya, vide supra). Not when A
is CH.dbd.CH--CH.sub.3 ; when A=NO.sub.2, it is simultaneously
reduced to NH.sub.2.
Aluminum triisopropoxide in isopropanol at a range from room
temperature to reflux.
Step 7i:
PtO.sub.2 in an alcohol or a mixture of chlorinated solvent and an
alcohol, under hydrogen pressure of 10 to 50 p.s.i. at a
temperature rang of from 20.degree. to 60.degree. C. Also, under
these conditions, when R.sub.2 =phenyl, this group may be reduced
to the corresponding analogue where R.sub.2 =cyclohexyl [See
Intermediate CXXXV].
Intermediates (6), (7) and (8) of Reaction Scheme 7 can be
transformed into the corresponding compounds having B (with the
same meanings as in Reaction Scheme 1) instead of A, according to
step 1g.
Reaction Scheme 8 shows the preparation of simple starting
materials such as (4), (5), (6) and (9), where A has the same
meanings as in Reaction Scheme 1. Intermediates (1), (2), (3), (7),
(8) can be prepared according to Reaction Schemes 1, 2, 4, 5, 7, 9,
and 11.
Steps 8a-8h have the following meanings:
Step 8a:
Pb(OAc).sub.4 in a suitable solvent (e.g., benzene, toluene) at
reflux (G. A. Russel et al., J. Am. Chem. Soc., 1906, (1975)).
Step 8b:
Sodium borohydride in alcohol (see Reaction Scheme 7, step 7a) then
alkaline hydrolysis (when A=COOR, it can be simultaneously
converted into COOH);
aluminum isopropoxide as described in Reaction Scheme 7, step
7h;
diborane in tetrahydrofuran at -10.degree. C./r.t. then aqueous
hydrogen peroxide in the presence of sodium hydroxide (not when A
is CH.dbd.CH--CH.sub.3 ; when A=COOR, it can be simultaneously
converted into COOH). (Kirkia-charian et al., C.R. Hebd. Seances
Acad. Sci. Ser. C, 289, 227, (1979));
lithium aluminum hydride and aluminum trichloride in a suitable
solvent (e.g., tetrahydrofuran) at 0.degree. C./reflux (not for
A=COOR or NO.sub.2) (Bokadia et al., J. Chem. Soc., 4663,
(1961)).
Step 8c:
Hydrogen (100 atm), copper chromite in ethanol at 140.degree. C.
(M. A. Vickars, Tetrahedron, 20, 2873, (1964)). When A is NO.sub.2
it is simultaneously converted into a NH.sub.2 group.
Step 8d:
Potassium permanganate in tert-butanol (or other suitable solvent)
in the presence of aqueous sodium hydroxide at
-10.degree./0.degree. C. (K. Hanaya, Bull. Chem. Soc. Jpn., 40,
1884, (1967)) (not when A is CH.dbd.CH--CH.sub.3). (See also A. H.
Haines, "Methods for the Oxidation of Organic Compounds", Academic
Press Inc, (London), 1985, chapter 3.2.2).
Osmium tetroxide (see A. H. Haines, vide supra, chapter 3.2.1) in a
suitable solvent (e.g., diethyl ether) at room temperature
(Baranton et al., Bull. Soc. Chim. Fr, 4203, (1968)) (not when A is
CH.dbd.CH--CH.sub.3);
aqueous hydrogen peroxide in formic acid or acetic acid at
-20.degree./-50.degree. C. then NaOH, H.sub.2 O, 45.degree. C.
(Baranton et al., vide supra; A. H. Haines, vide supra, chapter
3.2.7.) (not when A is CH.dbd.CH--CH.sub.3 ; when A=COOR it can be
simultaneously converted into COOH);
silver acetate and iodine in wet acetic acid at
0.degree.-20.degree. C. (K. Hanaya, vide supra; A. H. Haines, vide
supra, chapters 3.2.3, 3.2.4, 3.2.9) (not when A is
CH.dbd.CH--CH.sub.3).
Step 8e:
30% Hydrogen peroxide in the presence of sodium hydrogencarbonate
in benzonitrile at 0.degree.-110.degree. C., then lithium aluminum
hydride in tetrahydrofuran at 0.degree.-40.degree. C. (not for
A=COOR and CH.dbd.CH--CH.sub.3) (Clark et al., Austr. Journ. of
Chem., 27, 865 (1974)).
Step 8f:
Hydrogen (1-50 atm) in a suitable solvent (e.g., ethanol) in the
presence of a metallic catalyst (e.g., palladium dichloride) at
r.t. 78.degree. C. (when A=NO.sub.2 it is simultaneously converted
into NH.sub.2), (Bolger et al., Tetrahedron, 23, 341, (1967)).
Step 8g:
see step 8e (Clark et al., vide supra).
Step 8h:
Cerium trichloride heptahydrate 0.4M in methanol, in a suitable
solvent (e.g., methanol) then sodium borohydride at
0.degree./78.degree. C. (W089/06650);
sodium borohydride in diglyme at 0.degree. C./reflux (G. P. Thakar,
Indian J. Chem., 3, 74 (1965)) (when A=NO.sub.2 it can be converted
into NH.sub.2);
sodium borohydride-aluminum trichloride in a suitable solvent
(e.g., tetrahydrofuran or benzene) at 0.degree. C./reflux (not with
A=COOR) (G. P. Thakar, vide supra);
diborane in tetrahydrofuran at room temperature (not when A is
CH.dbd.CH--CH.sub.3) (G. P. Thakar, vide supra).
Intermediates (4), (5), (6), (9) of Reaction Scheme 8 can be
transformed into the corresponding compounds having B (with the
same meanings as in Reaction Scheme 1) instead of A, according to
step 1g.
Simple starting materials having W=CH.sub.2 and a single bond at
position 2-3 may be prepared according to Reaction Scheme 9 (where
A has the same meaning as in Reaction Scheme 1).
Intermediates (1) may be prepared according to Reaction Scheme 6 or
from Intermediate (2) (obtainable following Reaction Scheme 7)
converted into a 4-toluenesulfonic acid ester or a methanesulphonic
acid ester or into a halogen derivative (3), which may be
transformed into a thioether derivative (1) by nucleophilic
substitution with a thiol. These simple conversions can be
performed by techniques known to those skilled in the art.
Intermediates (3) where P=OC(S)aryl or OC(S)heteroaryl or
OC(S)O-alkyl, aryl or OC(S)S-alkyl may be obtained from (2) and the
appropriate chlorothioformate or chlorothiocarbonate or
1,1'-thiocarbonildiimidazole as described in J. Org. Chem., 55, 924
(1990) and Synthesis, 362, (1991) and references cited therein.
Intermediates (4) may be obtained from intermediates (1) or (3) by
simple elimination reaction with bases.
Intermediates (5) may be obtained according to Reaction Scheme
4.
Step 9a-9e of Reaction Scheme 9 have the following meanings:
Step 9a:
Raney-Ni in a suitable solvent (e.g. isopropanol) at
r.t./100.degree. C. When A=NO.sub.2 it is simultaneously converted
into NH.sub.2 ;
triethyltin hydride in benzene or other aromatic solvent at
30.degree.-150.degree. C. For other de-sulfurization methods, like,
e.g., nickel chloride and sodium borohydride in methanol or
borane-pyridine complex in trifluoracetic acid or in
dichloromethane in the presence of aluminum trichloride, see: J.
March, "Advanced Organic Chemistry", pg. 728, J. Wiley & Sons,
New York, 1992 and references cited therein. (not when A is
CH.dbd.CH--CH.sub.3).
Step 9b:
Hydrogen with a catalyst according to Reaction Scheme 8, step 8f.
When A=NO.sub.2, it is simultaneously converted into NH.sub.2.
Step 9c: Where P is an O-C derivative:
tributyltin hydride or tris(trimethylsilyl)silane (Sc-hummer D., et
al, SYNLETT, 11:705, 1990) in the presence of
azobisisobutyronitrile ("AIBN" used as a radical reaction initiator
and prepared according to C. G. Overberger et al, J. Am. Chem.
Soc., 71:2661, 1969) in a suitable solvent (e.g., toluene) at
80.degree.-150.degree. C.; (M. Drescher, Synthesis, 362, (1991). M.
Sekine, J. Org. Chem., 55, 924, (1990));
a silane (e.g., triethylsilane or diphenyl silane) in a suitable
solvent (e.g., dichloromethane) at -20.degree. C./reflux in the
presence of trifluoracetic acid or boron trifluoride (F. M. Mauser,
J. Org. Chem., 55, 555 (1990));
triethylchlorosilane, sodium iodide in acetonitrile then zinc
powder in acetic acid and acetonitrile at r.t./80.degree. C. (T.
Morita et al., Synthesis, 32, (1981)) Where P is halogen or an O-S
derivative:
a reducing agent (e.g., sodium cyanoborohydride in
hexamethylphosphotriamide or sodium borohydride in
dimethylsulfoxide) chosen from those cited in J. March, "Advanced
Organic Chemistry", J. Wiley, New York, (1992) chapter 0-76 or
0-77.
Step 9d:
Hydrogen (1-5 atm) in a suitable solvent (e.g., ethanol) in the
presence of a catalyst (e.g., palladium on carbon 10% at
50.degree.-78.degree. C.) (Sarcevic, Helv. Chim. Acta, 56, 1457,
(1973)) (When A=NO.sub.2 it is simultaneously converted into
NH.sub.2);
zinc and gaseous hydrochloride acid in diethyl ether or acetic
anhydride in toluene at 0.degree.-80.degree. C. (M. Toda, Bull.
Chem. Soc. Jp., 45, 264, (1972)) (not when A is NO.sub.2).
Step 9e:
Zinc and aqueous hydrochloric acid in a suitable solvent (e.g.,
ethanol) at 0.degree.-78.degree. C.;
according to step 9d above (when A=NO.sub.2, it is simultaneously
converted to NH.sub.2);
hydrazine, sodium hydroxide in ethane-1,2-diol at 200.degree. C.
(CA 74 (1971): 22699) (not for A=COOR, NO.sub.2) or other methods
cited in J. March, vide supra) (not for A=COOR, NO.sub.2);
according to step 7c of Reaction Scheme 7 (not for A=NO.sub.2).
The intermediates (6) of Reaction Scheme 9 can be transformed into
the corresponding compounds having B (with the same meanings as in
Reaction Scheme 1) instead of A, according to step 1g.
When X represents an oxygen atom or a sulphur atom and W represents
a bond, simple starting materials can be prepared according to the
following Reaction Scheme 10, wherein the steps 10a-10g have the
following alternative meanings:
Step 10a:
using the same conditions described for step 1a of the Reaction
Scheme 1 but utilizing R.sub.3 COCl or (R.sub.3 CO).sub.2 O instead
of R.sub.3 CH.sub.2 COCl or (R.sub.3 CH.sub.2 CO).sub.2 O, with or
without isolation of the intermediate phenyl ester;
hexamethylenetetramine in trifluoroacetic acid at reflux followed
by aqueous hydrochloric acid addition. Such strong acid conditions
might give Intermediates (2) having A=COOH, that need
re-esterification with the appropriate alcohol (e.g., using thionyl
chloride at reflux temperature) before Step 10c;
Step 10b:
R.sub.2 COCH(R.sub.3)Hal in acetone or methyl ethyl ketone or
dichloromethane or chloroform in the presence of a suitable base
such as potassium carbonate, triethylamine or sodium hydride, at
20.degree.-80.degree. C.;
Step 10c:
R.sub.2 CH(Hal)COOAlk in an aprotic solvent (e.g.,
dimethylformamide) in the presence of a base (e.g., potassium
carbonate) at 70.degree.-100.degree. C. followed by hydrolysis of
the remaining intermediates with a strong base (e.g., potassium
hydroxide) in aprotic solvent (e.g., ethyl alcohol) at reflux, and
finally submitting to decarboxylation - dehydration conditions
using a non-protic solvent (e.g., xylene) and an acid catalyst
(e.g., p-toluenesulfonic acid) at reflux or simply heating at
240.degree. C. in quinoline;
R.sub.2 CH.sub.2 Hal and potassium hydroxide in refluxing ethyl
alcohol followed by cyclization of the isolated intermediate
phenyl(thio)ether with sodium methoxide in a boiling
dimethylformamide-methanol mixture; when A=COOAlk, intermediates
(4) having A=COOH can be obtained.
Using ArCOCH.sub.2 Br and potassium carbonate in acetone at reflux,
Intermediates (4), having R.sub.2 =ArCO, are obtained.
Step 10d:
Vigorous stirring in preheated polyphosphoric acid at
90.degree.-140.degree. C.;
Lewis acid (e.g., aluminum trichloride) in chlorobenzene at
70.degree.-90.degree. C. The cyclizations carried out on
Intermediates (3) having R.sub.3 =Cl with a Lewis acid (e.g.,
aluminum trichloride) in o-dichlorobenzene at 45.degree. C. or with
boron trifluoride in diethyl ether at 20.degree.-25.degree. C.
gives the Intermediates (4) where R.sub.3 =OH, as reported by K.
Davies, J. Chem. Soc. (PT. 1), 2624, (1957) for compounds having
X=S and R.sub.2 =H.
Step 10e:
sodium alkoxide (1 equivalent) in the same alcohol used to prepare
the alkoxide at 0.degree.-90.degree. C.; when A=COOAlk it may be
suitable to use the corresponding AlkOH as solvent reaction.
When R.sub.2 =COOAlk and X=S, Intermediates (4) can be hydrolyzed
to the corresponding R.sub.2 =COOH with sulfuric-acetic acid
mixture, (if A=COOAlk is present, it also can give A=COOH), and can
be selectively decarboxylated with copper in anhydrous quinoline at
210.degree.-220.degree. C., to give Intermediates (4) where R.sub.2
=H according to J. Cooper et al., J. Chem Soc. (C), 3405
(1971).
Step 10f:
R.sub.2 CH.sub.2 XH and one equivalent of sodium in ethanol at
reflux or R.sub.2 CH.sub.2 XH with sodium hydrogencarbonate in
ethanol-water mixture at 60.degree.-90.degree. C.
Step 10g:
When A=COOAlk or NO.sub.2, the same methods described in Reaction
Scheme 1, step 1g can be used. It must be noted that reduction of
the NO.sub.2 group to the NH.sub.2 group by catalytic hydrogenation
can simultaneously afford hydrogenation of the double bond at
position 2-3, as reported by S. L. Meisel et al., "Heterocyclic
Compounds", Ed. Interscience Publ.: "Compounds with Condensed
Thiophene Rings", pg 34, (1954) and M. Ahmed, ibidem, Ed.
Wiley-Interscience: "Benzofurans", pg 56, (1974). When A=NO.sub.2
and R.sub.2 =COAr, the reduction carried out with hydrogen in the
presence of Pt on carbon as catalyst gives the 2,3-dihydro
Intermediates (5) where B=NH.sub.2 and R.sub.2 =CH.sub.2 Ar as
reported in WO 86 07,056 (1986); when A=CH.sub.3 and R.sub.2,
R.sub.3, R.sub.6 are not CH.sub.3 or R.sub.2 does not bear a
CH.sub.3 group, the compounds can be transformed into the
corresponding:
A=CH.sub.2 Br by reaction with N-bromosuccinimide in carbon
tetrachloride and 2,2'-azobisisobutyronitrile (Griesbaum, supra) or
benzoyl peroxide as catalysts at reflux;
A=CHO by reaction of the above Intermediates with
hexamethylenetetramine in refluxing chloroform followed by acid
hydrolysis of the salt in boiling acetic acid or by reaction of
Intermediates having A=CH.sub.3 with tetrabutylammonium dichromate
in refluxing chloroform according to Valenti et al, Arzneim.
Forsch., 40, 122 (1990);
A=COOH by oxidation of the above Intermediates (A=CHO) with silver
oxide in a mixture of protic aqueous solvent (e.g.,
ethanol-dimethylformamide at 0.degree.-70.degree. C. according to
H. R. Rodriguez et al. Tetrahedron, 24, 6587 (1968) or with
potassium permanganate in t-butyl alcohol in the presence of sodium
di-H-orthophosphate aqueous solution at 70.degree.-75.degree. C.
according to S. Masamune et al., Tetrahedron Letters, 27, 4537
(1986). Intermediates (4) of the above Reaction Scheme 10 having
R.sub.3 =C.sub.6 H.sub.5 or tert-butyl, R.sub.2 =H and X=O can be
transformed into the corresponding intermediates having R.sub.2
=C.sub.6 H.sub.5 or tert-butyl and R.sub.3 =H by reacting with
polyphosphoric acid at 132.degree. C. according to Davies et al. J.
Chem. Soc., 822 (1958). Intermediates (4) of the above Reaction
Scheme 10 having R.sub.2 =COAr and A=COOAlk can be transformed into
the corresponding intermediates having R.sub.2 =CH.sub.2 Ar and
A=COOAlk by hydrogenating with H.sub.2 in presence of 10% Pd on
carbon in protic solvents (e.g. ethanol, acetic acid) at 10-70 psi
and at a temperature of 10.degree.-60.degree. C.
When X represents a nitrogen atom and W has all claimed meanings,
except a bond, the simple starting materials may be prepared
according to the following Reaction Scheme 11, wherein the steps
have the following alternative meanings:
Step 11a:
EtOC(R.sub.2)=C(COOEt).sub.2 at 80.degree.-140.degree. C. without
solvents or in a polar solvent (e.g., isopropanol);
Step 11b:
R.sub.2 COCH(R.sub.3)COOAlk and p-toluenesulfonic acid or
methanesulfonic acid in a chlorinated solvent (e.g., chloroform or
dichloromethane) or aprotic solvent (e.g., benzene) at reflux under
azeotropic conditions;
Step 11c:
by heating Intermediates (2) in diphenyl ether in the presence of
p-toluenesulfonic acid or phosphoric acid or zinc oxide as
catalysts at 245.degree.-255.degree. C. according to Hung. Teljies
6251 (CA 79, 92026v (1973)); heating in a high boiling solvent
(e.g., diphenyl ether) followed by hydrolysis of the remaining
Intermediates (4) (R.sub.3 =COOEt) with a strong acid (e.g.,
hydrochloric acid) in a protic solvent (e.g., acetic acid) at
reflux to give Intermediates (4) where R.sub.3 =COOH. The above
isolated acids can be decarboxylated by heating in a high boiling
solvent (e.g., diphenyl ether) to give Intermediates (4) where
R.sub.3 =H according to R. Albrecht et al., Ber., 105, 3118
(1972);
Step 11d:
heating in a high-boiling solvent (e.g., diphenyl ether) at
255.degree. C.;
when R=Alk Intermediates (4) are obtained directly from
Intermediates (1), without isolation of Intermediates (3), by
condensation with R.sub.2 COCH(R.sub.3)COOAlk in polyphosphoric
acid at 90.degree.-150.degree. C. according to F. Piozzi et al.,
Gazz. Chim. It., 100, 678 (1970).
Step 11e:
Al/Hg amalgam in aqueous ethanol solution at reflux followed by
acidification with a strong acid (e.g., hydrochloric acid) and
treatment with iron trichloride at reflux according to W. A. Denny
et al., J. Med. Chem., 32, 396 (1989).
When A=COOAlk Intermediates (4) should be hydrolyzed to the
corresponding A=COOH before performing Step e.
When A=NO.sub.2, intermediates (5) having A=NH.sub.2 are
obtained;
Step 11f:
R.sub.2 CH.dbd.CHCHO and arsenic acid in a strong acidic medium
(e.g., concentrated sulfuric acid) and water at
105.degree.-115.degree. C. according to EP 206,802 (1986).
When A=COOAlk, Intermediates (1) should be hydrolyzed to the
corresponding A=COOH before performing Step f. All Intermediates
(1) have R=H and the obtained Intermediates (5) have R.sub.3
=H.
Step 11g:
R.sub.2 CH(Hal) - CH(R.sub.3)COOH in a protic solvent (e.g., water)
in the presence of a strong base (e.g., sodium hydroxide) at
100.degree.-125.degree. C., followed by cyclization of the isolated
Intermediates .beta.-anilinopropionic acids with preheated
polyphosphoric acid at 120.degree.-125.degree. C. or with
phosphorous pentoxide in a high-boiling aprotic solvent (e.g.,
xylene) at 120.degree.-140.degree. C. In some cases, it is useful
to start from Intermediates (1), where R=tosyl or other suitable
protective groups; the obtained Intermediates (6), where R=tosyl,
can be easily converted into Intermediates (6), where R=H, by
hydrolysis with a strong acid (e.g., hydrochloric acid) in a protic
solvent (e.g., acetic acid) at reflux. When A=COOAlk, Intermediates
(6) having A=COOH, are obtained.
Step 11h:
R.sub.2 CHO and ethylene in acetic acid and hydrochloric acid at
25.degree.-30.degree. C. according to K. D. Hesse, Liebigs Ann.
Chem., 741, 117 (1970). Where Intermediates (1) have R=H starting
materials (7), having R=R.sub.3 =H are obtained. Epichlorohydrin
followed by cyclization of the isolated anilinopropanol derivatives
in refluxing N,N-diethylaniline or ortho-dichlorobenzene in the
presence of a proton acceptor (e.g., triethylamine) according to S.
D. Boyd et al., J. Org. Chem., 30, 2801 (1965). In this case,
Intermediates (7) having R=R.sub.2 =H and R.sub.3 =OH are
obtained;
Step 11i:
by hydrogenation in presence of a catalyst (e.g., platinum oxide)
in a protic solvent (e.g., ethanol) at 20.degree.-30.degree. C. and
2-4 atm according to G. M. Coppola, J. Heter. Chem., 15, 645
(1978).
When A=NO.sub.2, Intermediates (7), having A=NH.sub.2 are
obtained.
Intermediates (4),(5),(6) and (7) thus obtained can be converted to
the corresponding derivatives having A=COOH or NH.sub.2 according
to the methods of Reaction Scheme 1, step 1g.
The synthesis of the simple Intermediates (7) of Reaction Scheme 11
having R=H and A=COOH can be also pursued using the method shown in
the Reaction Scheme 12:
Step 12a:
oxalyl chloride in a polar solvent (e.g., tetrahydrofuran) at
reflux followed by internal Friedel-Crafts acylation of the
remaining chlorooxalylamide with a Lewis acid (e.g., aluminum
trichloride) in a non polar solvent (e.g., carbon disulfide) at
reflux, according to EP 402,859 (1989);
Step 12b:
30-35% aqueous hydrogen peroxide and a strong base (e.g., sodium
hydroxide) in a polar solvent (e.g., water) at
20.degree.-30.degree. C. followed by addition of a strong acid
(e.g., hydrochloric acid), as reported in EP 402,859 (1989).
When X represents an amino group and W is a bond, the simple
starting materials may be prepared according to the following
Reaction Schemes 13 and 14, wherein A has the same meanings as in
Reaction Scheme 1 and the steps have the following alternative
meanings:
Step 13a:
ClCH.sub.2 C(Cl)=CH.sub.2 in the presence of potassium carbonate at
40.degree.-80.degree. C. according to L. Purdie, J. Chem. Soc. (C)
1970, 1126;
Step 13b:
R.sub.2 COHal in pyridine or in a chlorinated solvent (e.g.,
dichloromethane) in the presence of proton acceptor (e.g.,
triethylamine) at 20.degree.-100.degree. C. or in a polar solvent
(e.g., acetone) in the presence of potassium carbonate at
20.degree.-80.degree. C.;
Step 13c:
boron trifluoride in methyl alcohol at 130.degree.-155.degree. C.;
heating at 100.degree.-110.degree. C.
Intermediates (5) obtained by this route, have always R.sub.2
=CH.sub.3.
Step 13d:
R.sub.2 COCH(OAlk).sub.2 in a non- polar solvent (e.g., toluene) in
the presence of iodine as catalyst at reflux in azeotropic
conditions followed by reduction of the isolated (or unisolated)
imino intermediate with sodium borohydride in a polar solvent
(e.g., methanol) in the presence of sodium hydroxide (as catalyst)
at reflux. When A=COOAlk, Intermediates (6) having A=COOH can be
obtained;
Step 13e:
sodium amide in a high boiling solvent (e.g., N,N-diethylaniline)
at 220.degree.-250.degree. C. according to F. Piozzi et al., Gazz.
Chim. It., 93, 1382 (1963);
potassium t-butoxide in a polar solvent (e.g., dimethylformamide)
at 20.degree.-100.degree. C. according to EP 42,298 (1981);
Step 13f:
boron trifluoride in an apolar solvent (e.g., benzene) at
5.degree.-10.degree. C.;
Step 13g:
zinc or iron dust in acidic medium (e.g., acetic acid) and water at
70.degree.-100.degree. C.
When A=NO.sub.2, Intermediates (5) having A=NH.sub.2 are
obtained.
Step 13h:
thionyl chloride at reflux followed by reaction of the isolated
Intermediates (7) acyl chlorides with sodium azide in acidic medium
(e.g., acetic acid) at 10.degree.-20.degree. C. and subsequent
heating at 50.degree.-70.degree. C.;
Step 13i:
diazotation with sodium nitrite in concentrated sulfuric acid
followed by aqueous zinc chloride addition at 5.degree.-10.degree.
C. and by reaction of the isolated diazonium salts with CH.sub.2
=C(R.sub.2) COOH in a polar solvent (e.g., acetone) in the presence
of a copper salt (e.g., CuCl.sub.2) at 25.degree.-30.degree. C.
Examples of steps 13g,h,i are reported by A. Allais et al., Eur. J.
Med. Chem., 10, 187 (1975).
Step 13j:
R.sub.2 CH.sub.2 NO.sub.2 in a polar solvent (e.g., ethanol) in the
presence of a base (e.g., n-butylamine) and catalytic amounts of an
acid (e.g., acetic acid) at reflux.
The Intermediates (5) thus obtained can be converted to the
corresponding derivatives having A=COOH or NH.sub.2 according to
the methods of Reaction Scheme 1 step 1g.
With regard to Reaction Scheme 14, it is intended that
Intermediates (4) having R.sub.3 =H correspond to Intermediates (5)
of Reaction Scheme 13.
Step 14a:
sodium nitrite in aqueous acidic medium (e.g., hydrochloric acid)
at -5.degree./+5.degree. C.;
isoamyl nitrite in a polar solvent (e.g., ethanol) at
5.degree.-10.degree. C.;
Step 14b:
aqueous solution of sulfur dioxide at 0.degree.-10.degree. C.
according to Pfannstiel et al., Ber., 75, 1096 (1942);
triphenylphosphine and heating of the isolated phosphonium salt in
an aqueous-alcoholic hydrogen chloride solution at reflux according
to Horner et al., Ber., 85, 1073 (1953).
Step 14c:
R.sub.2 COCH(R.sub.3)Hal in a basic high boiling solvent (e.g.,
N,N-diethylaniline) at 160.degree.-180.degree. C. or by simply
heating without solvents at 180.degree. C.;
R.sub.3 COCH(R.sub.2)Hal in a polar solvent (e.g., acetone) in the
presence of a suitable proton acceptor (e.g., potassium carbonate)
at reflux followed by cyclization of the isolated
.beta.-anilinoketone intermediates with freshly melted zinc
chloride in aprotic solvent (e.g., ethanol) at reflux;
R.sub.2 CH(Hal)CN in the presence of boron trichloride and a Lewis
acid (e.g., titanium tetrachloride) in an apolar solvent (e.g.,
benzene) at reflux followed by cyclization of the isolated
2-amino-.alpha.-haloacetophenones intermediates with a suitable
reducing agent (e.g., sodium borohydride) in a polar medium (e.g.,
dioxanewater) at reflux, according to T. Sagusawa et al., J. Org.
Chem., 44, 578 (1979). By the above method, Intermediate (4),
having R.sub.3 =H are obtained;
R.sub.2 COCH(R.sub.3)Hal (half an equivalent) in a polar solvent
(e.g., methanol) at reflux followed by cyclization of the isolated
Schiff base intermediates with a strong acid (e.g., trifluoracetic
acid) at 20.degree.-30.degree. C.;
Step 14d:
R.sub.2 COCH.sub.2 R.sub.3 by heating at 100.degree. C. without
solvents or at reflux in a polar solvent (e.g., methanol) followed
by cyclization of the isolated hydrazone intermediates with
polyphosphoric acid at 100.degree.-130.degree. C. or by simply
heating in ethyleneglycol or aqueous formic acid or ethanolic
formic acid.
Cyclization can be also carried out by heating in ethanolic
hydrogen chloride at reflux or in a mixture of acetic and
hydrochloric acid at reflux or in orthophosphoric acid at
95.degree.-105.degree. C. or by simply heating with anhydrous zinc
chloride at 100.degree.-220.degree. C. When A=COOAlk, Intermediates
(4) having A=COOH can be obtained.
Step 14e:
borane-pyridine complex at 0.degree.-30.degree. C. followed by a
protonating agent addition (e.g., hydrochloric acid);
tin or zinc and aqueous hydrochloric acid at 50.degree.-100.degree.
C.;
sodium borohydride in the presence of a Lewis acid (e.g., aluminum
trichloride) in pyridine at 0.degree.-30.degree. C. or
alternatively in the presence of a salt like cobalt or zinc
chloride;
sodium cyanoborohydride in acetic acid at 20.degree.-80.degree.
C.;
hydrogen in the presence of a catalyst (e.g., Pt) in a polar
solvent (e.g., ethanol) at 20.degree.-80.degree. C. Other general
methods are reported by Houlihan in "Heterocyclic Compounds", part
one, Ed. Wiley-Interscience: "Indoles", page 462 (1972). When
A=NO.sub.2, Intermediates (4) can be reduced to the corresponding
Intermediates (5) having A=NH.sub.2 ;
Step 14f:
sodium hydride and RHal in an anhydrous polar solvent (e.g.,
dimethylformamide) at 20.degree.-80.degree. C.;
RHal in the presence of potassium carbonate in a polar solvent
(e.g., acetone) at reflux;
sodium amide and RHal in a polar anhydrous solvent (e.g.,
tetrahydrofuran) at low temperature (-70.degree. C.). Intermediates
(4), bearing other reactive groups such as NH.sub.2 or OH, have to
be protected using suitable protective groups which can be
selectively cleaved at the end by deprotecting methods;
Step 14g:
RHal in the presence of alkaline metal carbonates (e.g., potassium
carbonate) as reported by Houlihan in "Heterocyclic Compounds",
part two, Ed. Wiley-Interscience: "Indoles", page 90 (1972) and
references cited therein.
Intermediates (5), bearing other reactive groups such as NH.sub.2
or OH, have to be protected as reported above;
Step 14h:
tetrachloro-[1,4]-benzoquinone in a polar solvent (e.g., ethylene
glycol monomethyl ether) at reflux;
copper (II) chloride in pyridine at reflux according to Kikugawa et
al., J. Heter. Chem., 16, 1325 (1979). Intermediates (6) having
R.sub.2 and R.sub.3 other than H, can be reduced to the
corresponding starting materials (7) by lithium aluminum hydride
according to H. C. Printy et al., J. Am. Chem. Soc., 71, 3206
(1949).
Intermediates (4) of Reaction Scheme 14 having R.sub.2 =H and
R.sub.3 =OH may be obtained from Intermediates (7) of Reaction
Scheme 11 having R=R.sub.2 =H and R.sub.3 =OH by ring contraction
using an oxidant (e.g., sodium periodate) and a base (e.g., sodium
hydroxide) in aqueous ethanol at reflux according to S. D. Boyd et
al., J. Org. Chem., 30, 2801 (1965).
Starting materials (4), (5), (6) and (7) can be converted into the
corresponding A=COOH or NH.sub.2 according to the method of
Reaction Scheme 1, step 1g, and from these into the alternative
final products. When NH is present and might interfere on the
following reactions, it can be protected as reported in T. W.
Green's "Protective Groups in Organic Synthesis", Wiley
Interscience (1981). Alternatively, unreactive groups (e.g.,
NO.sub.2) can be converted to reactive ones (e.g., NH.sub.2) as a
final step of the pathway.
Starting materials having W=bond, X=amino and a carboxymethyl group
at position 7, can be obtained according to Reaction Scheme 15,
wherein the steps have the following alternative meanings:
Step 15a:
Hydrogen at 45 lbs. in the presence of 10% palladium on charcoal as
catalyst in water containing one equivalent of sodium hydroxide,
followed by diazotation with sodium nitrite in hydrochloric acid at
0.degree.-5.degree. C. and stannous chloride. Cyclization is
performed during acidification of the tin salt with hydrogen
sulfide and completed by refluxing in xylene according to H. E.
Baumgarten et al., J. Am. Chem. Soc., 82, 3977 (1960).
Step 15b:
R.sub.3 CH.sub.2 COR.sub.2 in the presence of an acid (e.g., acetic
acid) in a polar solvent (e.g., ethanol) at reflux as reported by
W. J. Welstead et al., J. Med. Chem., 22, 1074 (1979) for R.sub.2
=CH.sub.3 and R.sub.3 =C.sub.6 H.sub.5, where also step 15c and 15d
are reported;
Step 15c:
AlkOH at reflux in the presence of an hydrogen chloride stream
(AlkOH=lower alkanol, e.g., methanol, ethanol);
Step 15d:
a strong base (e.g., potassium hydroxide) in a polar solvent (e.g.,
water) at reflux.
The preparation of simple starting materials having R.sub.3
=hydroxyalkyl and/or the corresponding ethers can be carried out by
reacting either Intermediates (3) of Reaction Scheme 1,
Intermediates (2), (4) or (5) of Reaction Scheme 2, Intermediates
(4) of Reaction Schemes 6, 10 and 15, Intermediates (4) and (5) of
Reaction Scheme 11, Intermediates (5) of Reaction Scheme 13 and
Intermediates (4) and (6) of Reaction Scheme 14 having R.sub.3 =H,
CH.sub.3 according to the Reaction Scheme 16, wherein A and B have
the same meanings as in Reaction Scheme 1, R.sub.5 represents an H
or alkyl group and the steps 16a-16h have the following
meanings:
Step 16a: R.sub.3 =H, W=CO, CS (and no activated phenyl rings
present):
Formaldehyde and hydrogen chloride in water, ethanol or acetic acid
at 50.degree.-100.degree. C.;
Chloromethyl methyl ether and fuming sulfuric acid at
50.degree.-70.degree. C. (H. Nakazumi et al., Bull. Chem. Soc.
Jap., 57, 2323 (1984));
R.sub.3 =CH.sub.3, W=CO, CS, bond, (bicyclic ring=Quinoline) and no
other methyl groups in the molecule:
N-bromosuccinimide in presence of benzoyl peroxide or
2,2'-azobisisobutyronitrile (Griesbaum, supra) in carbon
tetrachloride at 50.degree.-80.degree. C.;
Step 16b:
R.sub.3 =H, W=bond, X=O, S, NH or N-Alk and no electron donating
groups are present on the other rings of the molecule:
Phosphorous oxychloride and dimethylformamide at
50.degree.-140.degree. C., or other Viismeyer-Haack reagents (see
Jutz, Adv. Org. Chem., 9, 225 (1976));
R.sub.3 =CH.sub.3, W=bond, X=O, S, NH or N-Alk and no other
CH.sub.3 groups are present
Irradiation with a Hg high-pressure lamp in a protic solvent (e.g.,
acetic acid) at 20.degree.-100.degree. C. as reported by Frasca et
al., Tetrahedron, 23, 603 (1973);
Step 16c:
Sodium or potassium acetate in aprotic solvents (e.g., acetone,
dimethylformamide) at 40.degree.-120.degree. C.;
Step 16d: R.sub.5 in Intermediates (5)=H:
A reducing hydride (e.g., sodium borohydride) in a polar solvent
(e.g., methanol or ethanol or dioxane) at 0.degree.-80.degree. C.;
R.sub.5 in Intermediates (5)=alkyl:
Alkyl magnesium bromide in aprotic solvents (e.g., diethyl ether,
tetrahydrofuran) at 0.degree.-60.degree. C.;
Step 16e:
Sodium or lithium hydroxide in protic solvents (e.g., alcohols,
water) or mixture thereof at 25.degree.-50.degree. C. (In this
case, when A=COOAlk it can be simultaneously hydrolyzed to
COOH);
Step 16f:
The same methods reported in step 1g of Reaction Scheme 1, but the
oxidation of CH=CHCH.sub.3 to COOH for compounds (5);
Step 16g:
A strong base (e.g., NaH) and an R.sub.4 -L reagent (where L is an
halogen atom or a tosyloxy group) in anhydrous aprotic solvents
(e.g., dimethylformamide or tetrahydrofuran) at
20.degree.-140.degree. C.;
Step 16h:
R.sub.4 OH and a base (e.g., Na, NaH) in excess R.sub.4 OH or in
aprotic solvents (e.g., dimethylformamide or tetrahydrofuran) at
20.degree.-140.degree. C.
The simple Intermediates (6) having an hydroxyalkyl group at
position 3 of the bicyclic heteroring, obtained in this way, can be
reacted as such or, alternatively, derivatized at the hydroxymethyl
group with known reagents and methods, so that said group does not
interfere in the further reaction steps necessary to prepare those
compounds of formula (I) which bear a protected hydroxyalkyl group
such as R.sub.3. The protected final compounds are finally
converted by deprotecting methods to compounds of formula (I)
having R.sub.3 =hydroxyalkyl group.
As used herein "prodrug" or "prodrug derivative" means a derivative
of a compound disclosed herein which, once administered to a host,
is converted into the compound disclosed herein. A "metabolite" of
a compound disclosed herein is an active derivative of a compound
disclosed herein which is formed when the compound is metabolized.
A "prodrug of a metabolite" means a compound which is metabolized
to the same metabolite as a compound disclosed herein.
Metabolites of compounds disclosed herein can be identified either
by administration of compounds disclosed herein to a host and
analysis of blood samples from the host, or by incubation of
compounds disclosed herein with hepatic cells in vitro and analysis
of the incubant. Both methods are well-known in the art.
Compounds defined as "prodrug derivatives" in the Summary of the
Invention may be prepared, for example, starting from the
corresponding hydroxy (method 1) or amidic (method 2) compounds by
the following methods:
Method 1:
by reacting with a chloroformate, an isocyanate or isothiocyanate,
a carbonyl chloride or bromide or another activated acid derivative
(e.g., anhydride) in a suitable solvent (e.g., chlorinated
solvents, dimethylformamide, tetrahydrofuran, dioxane,
acetonitrile, pyridine) in the presence or absence of a base such
as triethylamine, pyridine, 4-dimethylaminopyridine, sodium
hydroxide, potassium carbonate or 1,10-diazabicycloundecene at
-20.degree./100.degree. C.;
by reacting with a carboxylic acid in the same solvents as above,
in the presence of a condensing agent such as
N,N'-carbonyldiimidazole, carbodiimides or others known to the
people skilled in the art;
by reacting with a dialkyl or diaryl chlorophosphate or dialkyl
cyanophosphonate in the same conditions described above (for
examples of such derivatization methods see Examples 114, 120-122,
165 and S. O. Thorberg et al., J. Med. Chem., 30, 2008 (1987)).
Method 2:
Prodrug derivatives of "acidic" NH groups according to the Summary
of the Invention can be synthesized from the compounds of formula I
considered in the Summary by preparing an
N-hydroxy(substituted)methyl derivative and reacting the derivative
under the same conditions as described above for oxygen
derivatization. The intermediate N-hydroxy(substituted)methyl
derivative can be isolated or directly reacted to give the desired
compound. N-hydroxy(substituted)methyl derivatives of the type
Ny-CH(R.sub.1)OH where R.sub.1 =H, CCl.sub.3 can be obtained by
reacting the appropriate compounds of formula I with formaldehyde
or CCl.sub.3 CHO as described in H. E. Zaugg, Organic Reactions,
14, Chapter 2, 52 J. Wiley and Sons New York, 1965 or in J. P.
Chupp, J. Org. Chem., 28, 2592 (1963). In the case where R.sub.1
=phenyl, said compounds can be synthesized by reacting with
benzaldehyde and a cyclic amine (e.g., morpholine) in methanol or
dichloromethane-methanol 1:1 at 0.degree. C.-reflux and hydrolyzing
the intermediate with 0.1N hydrochloric acid at pH=4. (O.
Jacobseen, Annalen, 157, 243 (1884); H. Bundgaard et al., Int. J.
Pharm., 22, 45 (1984)).
Compounds of the type Ny-CH.sub.2 -B' (where B' has been described
in the Summary of the Invention) can be prepared by reacting
compounds of formula I with the appropriate secondary amine and
formaldehyde in a suitable solvent (e.g., methanol,
tetrahydrofuran) at 0.degree.-100.degree. C. (H. Bundgaard, Int. J.
Pharm., 21, 251 (1984) or P. Tramontin, Synthesis, 1973, 736 and
references cited therein).
Some examples of prodrugs can be found in Examples 114, 120-122 and
165. Examples of compounds that are considered metabolites (e.g. of
the compound of Ex. 11) are in Example 59, 85, 91, 126, 133, 139,
140 and 158. The prodrugs of the former examples also qualify as
prodrugs of the metabolites of the latter examples.
All the above described reaction pathways and steps are to be
intended as examples and are not limiting the scope of the
invention. A person skilled in the art would appreciate that
reagents used in the chemical transformations of polyfunctional
substrates may react with non-targeted groups present in the
molecule. For example, catalytic hydrogenation can transform nitro
groups into amino groups as desired, however, isolated double bonds
might be hydrogenated and halogen atoms may be removed. Likewise,
lithium aluminum hydride can reduce conjugated ketones to alkanes
as desired (e.g., step 7c in Reaction Scheme 7), however, it may
also reduce COOAlk groups to CH.sub.2 OH or NO.sub.2 groups to
--N.dbd.N--. The undesired side-reactions can be avoided or
minimized by choosing the appropriate conditions or by using
alternative reagents or different synthetic pathways.
Alternatively, the undesired intermediates may be transformed into
useful ones using methods known in the art.
DETAILED SYNTHESIS OF INTERMEDIATES
8-(3-Bromopropoxycarbonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate I)
30 g of 1,3-dibromopropane was added dropwise at ambient
temperature to a suspension of 30 g of
sodium3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150
ml of dimethylformamide and 35 ml of water. The reaction mixture
was stirred at ambient temperature for 5 days. 100 ml of water was
added and stirring was continued for a further 15 minutes. The
precipitate was filtered off by suction, washed with water and
purified by flash chromatography on silica gel, eluting with
chloroform:ethyl acetate 95:5. The collected fractions were
evaporated to dryness in vacuo and the residue was recrystallized
from ethanol to give 27.7 g of the title compound, m.p.
114.degree.-115.degree. C.
The benzopyran carboxylate salt used in the foregoing synthesis was
prepared by dissolving the corresponding acid (104 g) in hot
methanol (560 ml) and adding an aqueous solution (280 ml) of sodium
hydrogen carbonate (31 g). The solution was added with acetone (850
ml) yielding the desired salt, collected by suction (62 g,
m.p.>280.degree. C.). The corresponding acid was prepared as per
Da Re, P. et al., J. Med. Pharm. Chem. 2; 263, (1960).
8-Hydroxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate II)
467 ml of a 1.48N solution of sodium borohydride in anhydrous
dimethyl formamide was added over a period of 30 minutes, under
stirring at ambient temperature, to a solution of 100 g of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride
(prepared as described in Da Re, supra) in 1 liter of anhydrous
dimethylformamide. The reaction mixture was stirred for 2.5 hours
at ambient temperature. 88 ml of 2N aqueous hydrochloric acid
solution was added while maintaining the temperature at
0.degree.-5.degree. C. 102 ml of 12.7N aqueous sodium hydroxide
solution was then added. The mixture was poured into 6 liters of
water, stirred for 3 hours, and filtered on a Buchner funnel. The
filter cake was washed with 4N sodium hydroxide solution and then
with water. The resultant white solid was crystallized from
methanol to give 50 g of the title compound, m.p.
145.degree.-147.degree. C.
E-8-(2-carboxyvinyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate III)
A mixture of 7.92 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as
described in Uneyama, K. et al., Bull. Chem. Soc. Jap. 58.; 2361,
(1985)) 3.75 g of malonic acid and 0.46 ml of piperidine in 15 ml
of anhydrous pyridine was stirred at 100.degree. C. for 3 hours.
After cooling to 20.degree.-25.degree. C. the reaction mixture was
poured into a mixture of 90 g of crushed ice and 33 ml of
hydrochloric acid (d=1.18). The resultant precipitate was collected
by suction filtration, washed with water and crystallized twice
from 95% ethanol to give 5.5 g of the title compound, m.p.
226.degree.-229.degree. C.
E-8-(2-chlorocarbonylvinyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate IV)
A solution of 9.2 g of Intermediate III and 7.8 g of thionyl
chloride in 75 ml of toluene was refluxed for 3 hours. After
cooling to 20.degree.-25.degree. C. the resultant crystal was
collected by suction filtration, washed with acetone and dried in
vacuo to give 6.8 g of the title compound, m.p. (190)
196.degree.-198.degree. C. after recrystallization from
toluene.
8-Acetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate
V)
1.17 g of magnesium turnings, 7.4 ml of anhydrous ethanol and 0.2
ml of anhydrous carbon tetrachloride were placed in a round
bottomed flask under a stream of nitrogen. When the temperature
began to rise, 7.5 ml of anhydrous chlorobenzene was added,
followed by the slow dropping (25 minutes) of a solution of 5.28 ml
of anhydrous diethylmalonate and 3.5 ml of anhydrous chlorobenzene
in 16 ml of anhydrous ethanol. The reaction flask was heated to
75.degree. C. for two hours, cooled to 25.degree. C. and a solution
of 8.8 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl
chloride in 88 ml of anhydrous chlorobenzene was slowly added,
without exceeding 35.degree. C. The reaction mixture was further
stirred for two hours at 35.degree. C. and then cooled to 0.degree.
C. 13 ml of water and 1.9 ml of sulfuric acid (d=1.84) were added.
The solution obtained was decanted from the insoluble inorganic
matter and stripped in vacuo.
The crude acylmalonate obtained was refluxed for six hours with
10.4 ml of acetic acid, 7 ml of water and 1.3 ml of sulfuric acid
(d=1.84). After cooling, the solution was poured into iced water
and the precipitate was collected by suction filtration and washed
with aqueous sodium carbonate. Crystallization from 90% ethanol
gave 6.5 g of the title compound, m.p. 159.degree.-161.degree.
C.
8-Bromoacetyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate
VI)
A solution of 11.2 g of bromine in 250 ml of chloroform was added,
over a period of two hours at 20.degree.-25.degree. C., to a
solution of 19.5 g of the Intermediate V in 700 ml of chloroform.
After stirring for 1 hour at 20.degree.-25.degree. C., the solution
was washed with 400 ml of 2N aqueous sodium hydroxide solution and
then repeatedly with water, dried with anhydrous sodium sulfate and
stripped in vacuo. The crude product was treated with diethyl
ether, collected by suction filtration and crystallized from
acetone, yielding 16 g of the title compound, m.p
134.degree.-135.degree. C.
8-(2-Hydroxyethylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate VII)
The title compound was prepared in the same manner as Intermediate
XXXVI, but using 2-aminoethanol instead of 3-aminopropanol. m.p.
206.degree.-208.degree. C.
3-Methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-sulfonyl chloride
(Intermediate VIII)
A solution of 4.55 g of sodium nitrite in 12 ml of water was added
dropwise to a stirred mixture of 15.1 g of
8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as
described in Da Re, P. et al., Il. Farmac (Ed. Sci.) 11: 670, 1956)
in 150 ml of hydrochloric acid (d=1.18) at -5.degree. C. Stirring
was continued at 0.degree. C. for 30 minutes. The solution was
poured, over a period of 10 minutes and at -5.degree. to 0.degree.
C., into 120 ml of a 30% by weight solution of sulfur dioxide in
acetic acid containing 1.53 g of cupric chloride dihydrate and 13
ml of water. After 1 hour at 0.degree. C. and 1 hour at
20.degree.-25.degree. C., 300 ml of iced water was added to the
mixture. A precipitate formed and was collected by suction
filtration, washed with water and dried in a desiccator over sodium
hydroxide until of constant weight to give 18 g of crude title
product, m.p. 165.degree.-170.degree. C., for use without further
purification.
8-(3-Chloropropoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate IX)
This compound was prepared in the same manner as Intermediate XI,
but using 1-bromo-3-chloropropane instead of
1-bromo-2-chloromethane (m.p. 98.degree.-102.degree. C.) after
washing with petroleum ether:diethyl ether 7:3.
8-Acrylamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate
X)
A solution of 1.75 ml of acryloyl chloride in 15 ml of anhydrous
tetrahydrofuran was added dropwise at -10.degree. C. to a stirred
mixture of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
and 3 ml of triethylamine in 60 ml of anhydrous tetrahydrofuran.
After stirring at 0.degree. C. for 1 hour and at ambient
temperature for 1 hour, the reaction mixture was poured into water
and filtered under suction. The filter cake was washed with water.
Desiccation gave 5.5 g of the title compound, m.p.
229.degree.-230.degree. C.
8-(2-Chloroethoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XI)
A mixture of 7.52 g of
8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as
described in Da Re, P. et al., Ann. Chim., 1962, p.506 et seq.),
6.22 g of anhydrous potassium carbonate and 25.5 ml of
1-bromo-2-chloromethane in 70 ml of dimethylformamide was stirred
at 60.degree. C. for 25 hours. The mixture was cooled to
20.degree.-25.degree. C. and poured into 600 ml of water. The
organic solution, obtained by extraction with dichloromethane, was
washed with aqueous sodium chloride solution and dried on anhydrous
sodium sulfate. The solvents and excess 1-bromo-2-chloromethane
were evaporated off in vacuo to yield 8.8 g of the title compound,
m.p. 141.degree.-142.degree. C. after crystallization from
chloroform: hexane.
8-(2-Azidoethoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XII)
A mixture of 15.2 g of Intermediate XI and 6.24 g of sodium azide
in 150 ml of anhydrous dimethylformamide was stirred at
70.degree.-75.degree. C. for 12 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 1.5
liters of water and extracted with dichloromethane. The organic
solution was washed with aqueous sodium chloride solution and dried
on anhydrous sodium sulfate. The solvents were evaporated off in
vacuo. The residue was taken up in water, collected by suction
filtration and dried to give 14 g of the title compound, m.p.
119.degree.-120.degree. C.
8-[N-(2-hydroxyethyl)-N-methyl-carbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-benz
opyran (Intermediate XIII)
A solution of 1.6 ml of 2-methylamino-ethanol in 10 ml of water was
added dropwise over a period of 5 minutes to a suspension of 6 g of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and
1.52 g of potassium carbonate in 60 ml of acetone. After stirring
for 2.5 hours at 20.degree.-25.degree. C., the solvent was removed
in vacuo and the residue was taken up in 150 ml of acetone. The
mixture was refluxed for 15 minutes, and was then filtered. The
solvent was evaporated from the filtrate and the residue was
dissolved in 20 ml of dimethylformamide, treated with 14 ml of 1.4%
aqueous sodium carbonate solution, stirred for 30 minutes at
20.degree.-25.degree. C. and diluted by addition of 150 ml of
water. The mixture was extracted with chloroform and the organic
layer was washed with 0.5N aqueous hydrochloric acid solution and
then with water. The solution was dried over anhydrous sodium
sulfate and the chloroform was evaporated off. The resulting oil
was taken up in 200 ml of diethyl ether and stirred for 2 hours at
20.degree.-25.degree. C. The solids were collected by filtration
and crystallized from ethyl acetate to give 4.97 g of the title
compound, m.p. 128.degree.-130.degree. C.
8-(2-Chloroethylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XIV)
The title compound was prepared in the same manner as Intermediate
XXXVII, but using Intermediate VII in place of Intermediate XXXVI
and carrying out the reaction at ambient temperature, m.p.
181.degree.-182.degree. C. (ethyl acetate).
8-(N-methyl-2-chloro-ethylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyra
n (Intermediate XV)
A solution of 1.1 ml of thionyl chloride in 2 ml of dichloromethane
was added to a solution of 3.37 g of Intermediate XIII in 20 ml of
dichloromethane, and the mixture was stirred for 4 hours at ambient
temperature. Removal of the solvent gave an oil which was taken up
in diethyl ether. The title compound precipitated as a white solid
which was filtered off for use without further purification. m.p.
(118) 126.degree.-128.degree. C. (diethyl ether).
8-(4-Bromobutoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XVI)
A mixture of 5 g of
8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 4.2 g of
anhydrous potassium carbonate and 43.6 g of 1,4-dibromobutane in 45
ml of dimethylformamide was stirred at 75.degree. C. for 2 hours.
The mixture was cooled to 20.degree.-25.degree. C., poured into 100
ml of water and extracted with dichloromethane. The organic
solution was washed with aqueous sodium chloride solution and dried
on anhydrous sodium sulfate. The solvents and excess
1,4-dibromobutane were evaporated off in vacuo. The residue was
rinsed with 55 ml of petroleum ether:diethyl ether (7:4) and
collected by suction filtration to yield 5.6 g of the title
compound, m.p. 91.degree.-92.degree. C.
8-(5-Bromopentyloxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XVII)
This compound was prepared by the method described for the
preparation of Intermediate XVI, but using 1,5-dibromopentane in
place of 1,4-dibromobutane and purifying the crude product by
column chromatography on silica gel (elution with
dichloromethane:ethyl acetate (99:1). m.p. 75.degree.-76.degree.
C., after rinsing with petroleum ether:diethyl ether (30:4).
8-(2-Chloroethoxymethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XVIII)
6 ml of thionyl chloride in 18 ml of chloroform was added at
0.degree. C. to a stirred solution of 23 g of Intermediate XXII and
11 ml of triethylamine in 185 ml of chloroform. The reaction
mixture was warmed to 70.degree. C. and stirred for 2 hours. After
cooling to ambient temperature, it was poured into water. The
organic layer was separated, washed with aqueous sodium chloride
solution, dried on anhydrous sodium sulfate and evaporated to
dryness in vacuo. Yield: 24 g of the title compound. A sample
crystallized from ethanol had a melting point of
102.degree.-103.degree. C.
8-Chloromethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XIX)
53.4 g of Intermediate II and 38.8 ml of anhydrous triethylamine
were dissolved in 440 ml of chloroform. Into this solution,
maintained at -10.degree. to -2.degree. C., there was dropped a
solution of 19.8 ml of thionyl chloride in 80 ml of anhydrous
chloroform. The reaction mixture was stirred at room temperature
for 4 hours, and then diluted with 400 ml of water. The aqueous
phase was extracted with chloroform, and the extracts were added to
the chloroform phase. The chloroform solution was washed with
brine, dried on anhydrous sodium sulfate and evaporated to dryness
in vacuo. Yield: 56 g of the title compound, which on
recrystallization from ethanol was shown to have a melting point of
112.degree.-113.degree. C.
8-Methylaminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XX)
A solution of 15.1 g of anhydrous zinc chloride and 14.5 g of
sodium cyanoborohydride in 400 ml of anhydrous methanol was added
dropwise at 0.degree. C. into a stirred mixture of 58.8 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 60.7 g of
methylamine hydrochloride and 125 ml of triethylamine in 600 ml of
anhydrous methanol. After stirring for 5 hours at
20.degree.-25.degree. C., the solvent was evaporated off in vacuo
and the residue was taken up in 200 ml of water and collected by
suction filtration. The crude product was dissolved in aqueous
acetic acid, washed with ethyl acetate and re-precipitated by
addition of cold 6N aqueous sodium hydroxide solution. 49 g of the
title compound was obtained. m.p. 97.degree.-99.degree. C., after
crystallization from 75% ethanol.
8-(2-Chloroethylthiomethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXI)
A solution of 37 g of Intermediate XIX and 10.5 g of thiourea in
370 ml of ethanol was refluxed for 1 hour. The reaction mixture was
cooled to ambient temperature, and 42 g of
8-amidinothiomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
hydrochloride spontaneously crystallized. A sample recrystallized
from ethanol had a melting point of 233.degree.-235.degree. C.
48 ml of 35% aqueous sodium hydroxide solution was added to a
vigorously stirred suspension of 35 g of the compound thus prepared
and 1.05 g of benzyl triethylammonium chloride in 440 ml of
1,2-dichloroethane. The mixture was stirred for 2.5 hours and then
poured into 300 ml of water. The aqueous layer was extracted with
1,2-dichloroethane and the extracts were added to the organic layer
which was washed with sodium chloride solution, dried on anhydrous
sodium sulfate, and evaporated to dryness in vacuo. The residue was
crystallized from methanol, giving 22 g of the title compound, m.p.
82.degree.-83.degree. C.
8-(2-Hydroxyethoxymethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXII)
A solution of 2.5 g of Intermediate XIX in 25 ml of xylene and 3 ml
of dioxane was prepared. 0.15 g of sodium was dissolved in 3.10 ml
of anhydrous ethylene glycol, and this solution was added dropwise
at ambient temperature to the solution of Intermediate XIX. After
refluxing for 5.5 hours, the reaction mixture was cooled to ambient
temperature and poured into 50 ml of water. It was extracted with
dichloromethane, and the extract was washed with sodium chloride
solution, dried on anhydrous sodium sulfate and evaporated to
dryness in vacuo. The solid residue was crystallized from ethanol,
giving 2.1 g of the title compound, m.p. 132.degree.-133.degree.
C.
8-Trifluoroacetamido-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXIII)
A solution of 9.5 ml of trifluoroacetic anhydride in 20 ml of
anhydrous dichloromethane was added dropwise at
-5.degree.-0.degree. C. to a solution of 5 g of
8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 50 ml of
anhydrous dichloromethane. The reaction mixture was stirred for 2
hours at 20.degree.-25.degree. C. and then poured on to crushed
ice. The organic solution obtained by extraction with
dichloromethane was washed with cold 5% aqueous sodium bicarbonate
solution and with water, and was dried on anhydrous sodium sulfate.
The solvent was removed in vacuo and the residue was crystallized
from ethanol to give 5.2 g of the title compound, m.p.
175.degree.-176.degree. C.
8-Aminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate
XXIV)
A mixture of 21 g of Intermediate XXIX and 19 g of
triphenylphosphine in 160 ml of tetrahydrofuran was stirred at
ambient temperature for 8 hours. Thin layer chromatography showed
the disappearance of Intermediate XXIX. 3 ml of water was added,
and stirring was continued for a further 24 hours. The solvents
were removed on a rotary evaporator, and the residue was dissolved
in water as its acetate. The aqueous solution was washed with ethyl
acetate, made basic with 37% aqueous sodium hydroxide solution and
filtered on a Buchner funnel. The filter cake was washed with water
and desiccated to give 18 g of the title compound. The
hydrochloride, recrystallized from ethanol, had a melting point of
256.degree.-258.degree. C.
8-(2-Chloroethylsulfonylmethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXV)
41.6 ml of aqueous 30% hydrogen peroxide was added dropwise at
40.degree. C. over a period of 20 minutes to a solution of 26.2 g
of Intermediate XXI in 300 ml of glacial acetic acid. The mixture
was heated to 60.degree. C., stirred at that temperature for 4.5
hours, cooled to ambient temperature and poured into 60 ml of
water. Filtration on a Buchner funnel gave a filter cake which was
washed with water and desiccated, yielding 29.4 g of the title
compound. A sample was crystallized from ethanol. m.p. (89)
159.degree.-161.degree. C.
8-(2-Chloroethylsulfinylmethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXVI)
36 ml of aqueous 30% hydrogen peroxide was quickly added dropwise
at 10.degree. C. to a solution of 12 g of Intermediate XXI in 84 ml
of glacial acetic acid. The reaction mixture was stirred for 4
hours at ambient temperature, and then poured into 220 ml of water.
The title compound was collected by suction filtration, washed with
water and desiccated. Yield 12.4 g, m.p. 142.degree.-145.degree. C.
(methanol).
8-[N-methyl-N-(2-chloroethyl)-aminomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-ben
zopyran (Intermediate XXVII)
A mixture of 22 g of Intermediate XX, 66 ml of
1-bromo-2-chloroethane and 11 g of anhydrous potassium carbonate in
88 ml of dimethylformamide was stirred at 20.degree.-25.degree. C.
for 12 hours. The reaction mixture was then poured into 600 ml of
water and extracted with dichloromethane. The organic layer was
washed with water, dried on anhydrous sodium sulfate and acidified
with ethanolic hydrogen chloride. The solvent and the excess
1-bromo-2-chloroethane were distilled off in vacuo at
70.degree.-80.degree. C. The residue was taken up in cold 1N
aqueous sodium hydroxide solution and extracted with
dichloromethane. The organic solution was washed with water, dried
on anhydrous sodium sulfate and evaporated to dryness in vacuo at
25.degree.-30.degree. C. The crude title product was purified by
flash chromatography on silica gel, eluting with ethyl
acetate:petroleum ether (7:3), to give 18 g of the title compound
melting at 118.degree.-120.degree. C. after crystallization from
ethanol.
1-(2-Hydroxy-2-methylpropyl)-4-(2-methoxyphenyl)-piperazine
(Intermediate XXVIII)
A mixture of 7 g of 1-(2-methoxyphenyl)-piperazine, 7.33 g of
anhydrous potassium carbonate, 1.75 g of potassium iodide and 5.6
ml of 1-chloro-2-methyl-2-propanol was stirred for 90 minutes at
70.degree. C. and for a further 6 hours at 90.degree. C. The
reaction mixture was poured into iced water and extracted with
ethyl acetate. The organic layer was washed with aqueous sodium
chloride solution, dried on anhydrous sodium sulfate and evaporated
to dryness in vacuo. The title product was obtained as an oil, and
was characterized as its dihydrochloride, crystallized from
ethanol, melting at 225.degree.-227.degree. C.
8-Azidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate
XXIX)
A mixture of 22.8 g of Intermediate XIX and 6.8 g of sodium azide
in 110 ml of dimethylformamide was stirred for 3 hours at
100.degree. C. After cooling to ambient temperature, 130 ml of
water and 88 ml of ethanol were added to the reaction mixture.
After 1 hour, the crystals were collected by vacuum filtration,
washed with water, and desiccated. Yield: 22 g of the title
product. A sample recrystallized from ethanol had a melting point
of 132.degree.-134.degree. C.
8-[N-(2-hydroxyethyl)-aminomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXX)
A solution of 2.38 g of anhydrous zinc chloride and 2.30 g of
sodium cyanoborohydride in 71 ml of anhydrous methanol was added
dropwise under stirring to a mixture of 9.24 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.12 g of
ethanolamine in 90 ml of anhydrous methanol. Stirring was continued
at 20.degree.-25.degree. C. for 5 hours, before removal of the
solvent in vacuo. 250 ml of water was added to the residue, and the
insoluble matter was collected by suction filtration and washed
with water. The crude product was dissolved in 1N aqueous acetic
acid solution and the solution was washed with ethyl acetate. The
aqueous solution was then made alkaline by addition of 2N aqueous
sodium hydroxide solution and the precipitate was collected by
suction filtration and washed with water to give 8.5 g of the title
compound, m.p. 117.degree.-121.degree. C. after drying at
60.degree. C.
8-(N-methyl-N-chloracetyl-aminomethyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopy
ran (Intermediate XXXI)
A solution of 6 ml of chloracetyl chloride in 60 ml of
1,2-dichloroethane was added dropwise at -5.degree. to 0.degree. C.
to a solution of 20 g of Intermediate XX and 10 ml of triethylamine
in 200 ml of 1,2-dichloroethane. After stirring at
20.degree.-25.degree. C. for 2 hours, 150 ml of water was added to
the reaction mixture and the phases were separated. The organic
phase was washed with water and dried on anhydrous sodium sulfate.
The solvent was removed in vacuo, and the residue was crystallized
from ethanol to give 22.5 g of the title compound, m.p.
146.degree.-148.degree. C.
8-Chloracetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXXII)
A solution of 3.2 ml of chloracetyl chloride in 32 ml of
1,2-dichloroethane was added dropwise, under stirring at -5.degree.
C., to a mixture of 10 g of Intermediate XXIV and 5.5 ml of
triethylamine in 80 ml of 1,2-dichloroethane. The reaction mixture
was stirred at ambient temperature for 1 hour and then 150 ml of
water was added. The phases were separated; the aqueous phase was
extracted with 1,2-dichloroethane and the extracts were added to
the organic phase which was then washed with a cold saturated
solution of sodium bicarbonate, washed with water, dried on
anhydrous sodium sulfate and evaporated to dryness in vacuo. The
residue was crystallized from ethanol to give 10.7 g of the title
compound, m.p. 152.degree.-155.degree. C.
8-[N-acetyl-N-(2-chloroethyl)-aminomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-ben
zopyran (Intermediate XXXIII)
8.65 g of Intermediate XXX and 4.15 ml of triethylamine were
dissolved in 70 ml of tetrahydrofuran. To this solution, at
-10.degree. C., there was added dropwise over a period of 40
minutes a solution of 2.35 ml of acetyl chloride in 23 ml of
tetrahydrofuran. After stirring for 3 hours at 0.degree.-10.degree.
C. and for 2 hours at 20.degree.-25.degree. C., the solvent was
evaporated off in vacuo.
100 ml of water was added to the residue, and extraction with
dichloromethane was effected, pooling the successive organic
extracts and then removing the solvent in vacuo. The residue was
dissolved in 50 ml of methanol and 3 g of potassium carbonate and
10 ml of water were added. After stirring at 50.degree. C. for 20
minutes, to hydrolyse the N,O-diacetyl derivative which had formed,
the solvent was removed in vacuo and the residue was treated with
water and dichloromethane as above described. The dichloromethane
solution was again evaporated to dryness, and 5.9 g of
8-[N-acetyl-N-(2-hydroxyethyl)-aminomethyl]-3-methyl-4-oxo-2-phenyl-4H-1-b
enzopyran, m.p. 171.degree.-172.degree. C., was obtained.
3.6 ml of thionyl chloride in 30 ml of dichloromethane was added
dropwise at 0.degree. C. to a solution of 6.1 g of the compound
thus prepared in 70 ml of dichloromethane. After stirring for 90
minutes at 20.degree.-25.degree. C., the reaction mixture was
washed with water and dried. The solvent was removed in vacuo to
give the crude title product for use without further
purification.
8-(3-Chloropropylthio)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXXIV)
A solution of 20.1 g of stannous chloride dihydrate in hydrochloric
acid (d=1.18) was added over a period of 5 minutes at 65.degree. C.
to a solution of 6 g of Intermediate VIII in 70 ml of acetic acid.
After 10 minutes, the reaction mixture was cooled to
30.degree.-35.degree. C. and the solvent was removed in vacuo. The
residue was taken up in water, and the insoluble matter was
collected by suction filtration, washed with water and dried. Yield
3.2 g of 8-mercapto-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, m.p.
115.degree.-118.degree. C. after crystallization from ethanol.
A mixture of 8 g of the compound so prepared, 27 ml of
1-bromo-3-chloro-propane, 0.2 g of tetrabutylammonium bromide and
6.2 ml of 35% sodium hydroxide in 80 ml of benzene was vigorously
stirred for 4 hours at 20.degree.-25.degree. C. 100 ml of water and
40 ml of dichloromethane were added. The organic layer was
separated off, washed with water and dried on anhydrous sodium
sulfate. The solvents and excess 1-bromo-3-chloro-propane were
removed in vacuo. The residue was purified by column chromatography
on silica gel, eluting with petroleum ether:ethyl acetate 9:1, and
5.7 g of the title compound was obtained. After crystallization
from methanol, it showed a melting point of 84.degree.-86.degree.
C.
8-(3-Chloropropylsulfonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXXV)
7 ml of 30% hydrogen peroxide was added at 20.degree.-25.degree. C.
to a solution of 3.65 g of Intermediate XXXIV in 35 ml of acetic
acid. After stirring for 4 hours at 60.degree. C., the reaction
mixture was cooled to 20.degree.-25.degree. C. 30 ml of water was
added. A precipitate formed, and was collected by suction
filtration, washed with water and dried, yielding 3.4 g of the
title compound. After crystallization from acetone, it showed a
melting point of 160.degree.-163.degree. C.
8-(3-Hydroxypropylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXXVI)
A solution of 7.6 ml of 3-aminopropanol in 50 ml of water was added
dropwise over a period of 30 minutes to a suspension of 30 g of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and
15.2 g of potassium carbonate in 400 ml of acetone. The thick
suspension was stirred for 3 hours at 20.degree.-25.degree. C. The
solvents were removed in vacuo and the residue was taken up in 300
ml of water. After stirring for 1 hour, the precipitate was
collected by suction filtration and washed with water. The crude
product was purified by crystallization from 95% ethanol and 23.8 g
of the title compound were obtained, m.p. 191.degree.-193.degree.
C. An additional 4.7 g of the title compound was obtained by
concentration in vacuo of the crystallization filtrate.
8-(3-Chloropropylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XXXVII)
A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform was
added to a boiling solution of 3.37 g of Intermediate XXXVI in 20
ml of chloroform. After stirring for 90 minutes under reflux, the
solvent was removed in vacuo and the residue was crystallized from
acetonitrile to give 3 g of pure title compound, m.p. (188)
193.degree.-194.degree. C.
8-[1-Hydroxy-4-(4-methylphenylsulfonyloxy)-butyl]-3-methyl-4-oxo-2-phenyl-4
H-1-benzopyran (Intermediate XXXVIII)
1.12 g of sodium cyanide in 3 ml of water was added at
20.degree.-25.degree. C. to a stirred mixture of 3.96 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 2.61 g of
morpholine and 4.48 g of p-toluenesulfonic acid in 20 ml of
tetrahydrofuran and 30 ml of 1,2-dichloroethane. The reaction
mixture was refluxed for 4 hours, and then 10 ml of cold water was
added. The tetrahydrofuran was distilled off at normal pressure,
and 10 ml of 1,2-dichloroethane and 10 ml of chloroform were added.
The organic phase was separated, washed with aqueous sodium
chloride solution, dried over anhydrous sodium sulfate and
evaporated to dryness in vacuo. The residue was suspended in
diethyl ether, filtered off, and crystallized from chloroform:ethyl
acetate. Yield: 3.55 g of
8-(N-morpholinyl)cyanomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,
m.p. 236.degree.-238.degree. C.
3.5 ml of a 30% solution of potassium hydroxide in anhydrous
methanol was added under stirring at ambient temperature to a
suspension of 22.8 g of the compound thus prepared in 520 ml of
anhydrous tetrahydrofuran. 6.3 ml of acrylonitrile in 20 ml of
tetrahydrofuran was dropped into this suspension, and the reaction
mixture was stirred at ambient temperatures for 1 hour. The
solvents were evaporated off in vacuo. Crystallization of the
residue from methanol gave 23.22 g of
8-(1,3-dicyano-1-morpholinopropyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
23.2 g of the compound thus prepared was dissolved in 250 ml of
dioxane. 250 ml of 6M hydrochloric acid was added and the mixture
was refluxed for 2.pi. hours. After cooling to ambient temperature,
the mixture was poured into 700 ml of aqueous sodium chloride
solution and extracted with ethyl acetate. The extracts were washed
with aqueous sodium chloride solution and treated with 700 ml of 1M
sodium hydroxide solution. The aqueous layer was washed with ethyl
acetate and acidified with 37% hydrochloric acid. The precipitate
was collected by suction filtration and crystallized from ethanol
to give 10.2 g of
8-(3-carboxy-1-oxopropyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,
m.p. 191.degree.-192.degree. C.
Diborane, generated by dropping a solution of 2.1 ml of freshly
distilled boron trifluoride diethyl etherate in 10 ml of anhydrous
diglyme into 19 ml of a 0.66M solution of sodium borohydride in
diglyme, was bubbled into a suspension of 2.28 g of the compound
thus prepared in 23 ml of anhydrous tetrahydrofuran, stirred at
0.degree. C. under nitrogen flux. Stirring was continued for 20
minutes at 0.degree. C. and for a further 20 minutes at ambient
temperature. Methanol was cautiously dropped into the mixture at
0.degree. C. to quench the reaction. The solvents were removed by
evaporation in vacuo. The residue was purified by flash
chromatography on silica gel, eluting with petroleum ether:ethyl
acetate (3:7). The collected fractions were evaporated in vacuo to
leave 2 g of
8-(1,4-dihydroxybutyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,
m.p. 133.degree.-134.degree. C.
2.8 g of p-toluenesulfonyl chloride was added at 0.degree. C. to a
stirred solution of 3.17 g of the compound thus prepared in 32 ml
of anhydrous pyridine. The mixture was stirred for 6 hours at
0.degree. C. and stood overnight at -4.degree. C. without stirring.
It was then poured into 200 ml of aqueous sodium chloride solution,
acidified with 10 ml of 12N hydrochloric acid and filtered under
suction. The filter cake was dissolved in chloroform, and the
solution was washed with aqueous sodium chloride solution and dried
on anhydrous sodium sulfate. The solvent was distilled off in a
rotary evaporator. The residue was purified by flash chromatography
on silica gel, eluting with petroleum ether:ethyl acetate (1:1).
The collected fractions were evaporated to dryness in vacuo,
yielding 3.04 g of pure title product, m.p. 123.degree.-124.degree.
C.
4-[4-(2-Methoxyphenyl)-1-piperazinyl]-butyraldehyde (Intermediate
XXXIX)
A solution of 5.4 g of 2-(3-chloropropyl)-dioxolan and 15.9 g of
1-(2-methoxyphenyl)-piperazine in 60 ml of dimethylformamide was
stirred at 80.degree. C. for 4 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 500
ml of ice cold 0.5N aqueous sodium hydroxide solution and extracted
with dichloromethane. The organic phase was washed with water and
dried on anhydrous sodium sulfate. The solvent was removed in
vacuo, and the residue was purified by flash chromatography on
silica gel, eluting with dichloromethane:ethanol (95:5). 9.8 g of
2-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-dioxolan was
obtained as an oil.
NMR CDCl3 (.delta.) 1.5-2.0 (4H, m, CH.sub.2 CH.sub.2 CH) 2.2-3.2
(10H, m, 5.times.CH.sub.2 N) 3.7-4.0 (7H, m, OCH.sub.3 and
2.times.OCH.sub.2) 4.8 (1H, t, OCHO) 6.7-6.9 (4H, m, aromatic
protons)
A solution of 12.8 g of the compound thus prepared in 200 ml of
tetrahydrofuran and 420 ml of 1N aqueous hydrochloric acid solution
was maintained at 20.degree.-25.degree. C. for 24 hours. It was
then made alkaline with 5N aqueous sodium hydroxide solution and
immediately extracted with dichloromethane. The organic layer was
washed with water and dried on anhydrous sodium sulfate. The
solvent was evaporated off in vacuo, and the residue was purified
by flash chromatography on silica gel, eluting with
dichloromethane: methanol (97:3). 6.4 g of the title compound was
obtained as an oil.
NMR CDCl3 (.delta.) 1.5-2.0 (2H, m, CH.sub.2 CH.sub.2 CH.sub.2)
2.2-2.8 (8H, m, 3.times.CH.sub.2 N and CH.sub.2 CHO) 2.9-3.2 (4H,
m, 2.times.CH.sub.2 NAr) 3.8 (3H, s, OCH.sub.3) 6.8 (4H, s,
aromatic protons) 9.3 (1H, s, CHO).
8-(2,3-Epoxypropoxy)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XL)
7 ml of 2,3-epoxypropyl chloride was added dropwise at
20.degree.-25.degree. C. to a stirred mixture of 5 g of
8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 9.7 ml of 2N
aqueous sodium hydroxide solution in 10 ml of ethanol. After 6
hours at 20.degree.-25.degree. C., the reaction mixture was poured
into 100 ml of water and the precipitate which formed was collected
by suction filtration. After drying and purifying by flash
chromatography on silica gel (eluant petroleum ether: ethyl acetate
(65:35), there was obtained 4.45 g of the title compound, m.p.
128.degree.-129.degree. C.
8-[N-methyl-2-(4-methylphenylsulfonyloxy)ethylsulfamyl]-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran (Intermediate XLI)
A solution of 5 g of Intermediate VIII in 60 ml of dichloromethane
and 20 ml of tetrahydrofuran was added dropwise at 0.degree. C. to
a mixture of 2.5 ml of 2-methylaminoethanol and 2.1 ml of
triethylamine in 20 ml of dichloromethane. After stirring for 2
hours at 20.degree.-25.degree. C., 100 ml of water and 100 ml of
dichloromethane were added to the reaction mixture. The phases were
separated and the organic solution was dried on anhydrous sodium
sulfate. The solvent was removed in vacuo, and the residue was
purified by column chromatography on silica gel, eluting with
petroleum ether:ethyl acetate (3:7). There was thus obtained 4.5 g
of
8-(N-methyl-2-hydroxyethyl-sulfamyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyr
an, melting at 146.degree.-147.degree. C. after crystallization
from ethanol.
The compound thus prepared was converted to the title compound by
p-toluene sulfonylation according to the second step of the
procedure described below for the preparation of Intermediate
27469. The title compound was used without further
purification.
8-[2-(4-Methylphenylsulfonyloxy)-ethylsulfamyl]-3-methyl-4-oxo-2-phenyl-4H-
1-benzopyran (Intermediate XLII)
A solution of 5 g of Intermediate VIII in 37 ml of tetrahydrofuran
was added dropwise at 0.degree. C. to a mixture of 2.5 ml of
ethanolamine and 2.5 ml of triethylamine in 25 ml of
tetrahydrofuran. After stirring at 20.degree.-25.degree. C., the
reaction mixture was poured into 400 ml of water. A precipitate
formed, and was collected by suction filtration, washed with water
and air dried, yielding 4.6 g of
8-(2-hydroxyethylsulfamyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran,
melting at 186.degree.-187.degree. C. after crystallization from
ethyl acetate.
2.1 g of p-toluenesulfonyl chloride was added portionwise at
0.degree. C. to a solution of 3.6 g of the compound thus prepared
in 25 ml of pyridine. After 6 hours at 20.degree.-25.degree. C.,
the reaction mixture was slowly poured on to crushed ice containing
a slight excess of hydrochloric acid. A precipitate formed and was
collected by suction filtration and washed with water. 4.9 g of the
title compound was obtained, melting at (163)
166.degree.-169.degree. C. after crystallization from ethyl
acetate.
8-(3-Aminopropylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
hydrochloride (Intermediate XLIII)
A solution of 21.6 g of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 250
ml of anhydrous tetrahydrofuran was dropped at 0.degree.-10.degree.
C. into a stirred solution of 17 g of
3-(2-methyl-2-propoxycarbamoyl)-propylamine (prepared as described
in Saari, W. S. et al., J. Med. Chem. 33: 97, 1990) and 13 ml of
triethylamine. After stirring for 2 hours at ambient temperature,
the reaction mixture was poured into water and filtered to recover
12.3 g of
N,3-(2-methyl-2-propoxycarbamoyl)-propyl-3-methyl-4-oxo-2-phenyl-4H-1-benz
opyran-8-carboxamide which was recrystallized from ethanol, m.p.
178.degree.-180.degree. C.
A solution of 4.3 ml of trifluoroacetic acid in 15 ml of anhydrous
dichloromethane was added dropwise at -5.degree. C. under stirring
to a solution of 3.3 g of the compound thus prepared in 35 ml of
anhydrous dichloromethane. After warming to ambient temperature,
the mixture was stirred for 8 hours. The dichloromethane and the
excess trifluoroacetic acid were evaporated off at
20.degree.-25.degree. C. using a rotary evaporator. The oily
residue was dissolved in dichloromethane and 1N aqueous sodium
hydroxide solution was added. The organic layer was washed with
water, dried on anhydrous sodium sulfate and filtered. Excess
ethanolic hydrogen chloride was added to the filtrate, and the
solvent was removed in vacuo. The residue was crystallized from
ethanol to give 1.5 g of the title compound, m.p.
253.degree.-255.degree. C.
8-(2-Chloroethylureido)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XLIV)
4 ml of 2-chloroethylisocyanate were added, under stirring at
ambient temperature, to a solution of 3.9 g of
8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 52 ml of
anhydrous dimethylformamide. Stirring was continued at 70.degree.
C. for 5 hours. Water was added to the reaction mixture, which was
then extracted with ethyl acetate. The organic phase was evaporated
to dryness in vacuo. The residue was suspended in diethyl ether
under stirring. The title product was then filtered off and
recrystallized from methanol. Yield 3.74 g, m.p.
213.degree.-214.degree. C.
(Z,E)-8-{4-[2-(1,3-dioxanyl)]-1-butenyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzo
pyran (Intermediate XLV)
1.6 ml of 2.5N butyl lithium in hexane was added dropwise at
-20.degree. C. to a solution of 1.53 g of
2-[2-(1,3-dioxanyl)]-ethyl triphenylphosphonium bromide in 10 ml of
anhydrous tetrahydrofuran. The mixture was stirred for 20 minutes
at -20.degree. C. A solution of 0.8 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 11 ml of
anhydrous tetrahydrofuran was dropped into the mixture, which was
then warmed to 0.degree. C. over a period of 90 minutes and then to
ambient temperature over a period of 30 minutes. The reaction was
quenched by addition of methanol. The solvents were evaporated off
in vacuo and the residue was purified by flash chromatography on
silica gel, eluting with ethyl acetate:petroleum ether (3:7), to
give the title compound, as a mixture of diastereoisomers E and Z,
m.p. (93) 98.degree.-100.degree. C. The ratio of the two isomers
was determined by NMR spectroscopy and resulted E:Z=65:35.
NMR, CDCl.sub.3 (.delta.) 8.1-8.2 (m, 1H) CH in position 5 of the
benzopyran ring 7.2-7.8 (m, 7H) other aromatic CH groups of the
benzopyran and phenyl rings 6.9 (dt, 1H) Fl'-CH of the E isomer 6.8
(dt, 1H) Fl'-CH of the Z isomer 6.4 (dt, 1H) Fl'--CH.dbd.CH of the
E isomer 5.9 (dt, 1H) Fl'--CH.dbd.CH of the Z isomer 4.6-4.7 (m,
1H) OCHO 3.6-4.2 (m, 4H) CH.sub.2 O of the dioxane ring 2.4-2.7 (m,
2H) CHCH.sub.2 CH 1.9-2.3 (m, 5H) CH.sub.3 and CH.sub.2 in position
5 of the dioxane ring
8-{4-[2-(1,3-Dioxanyl)]-butyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XLVI)
A mixture of 0.2 g of 10% palladium-on-carbon catalyst and of 1 g
of Intermediate XLV in 24 ml of methanol was hydrogenated in a Parr
apparatus at ambient temperature with a hydrogen pressure of 1.5
atmospheres. After the theoretical hydrogen consumption, the
catalyst was filtered off and the solvent was removed by
evaporation in vacuo. The residue was crystallized from cyclohexane
to give the title compound, m.p. 118.degree.-119.5.degree. C.
8-Carboxymethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XLVII)
4.5 g of potassium permanganate was added portionwise within 1.5
hours under stirring at 0.degree.-10.degree. C., to a mixture of
2.76 g of 8-allyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (P. Da
Re, U.S. Pat. No. 3,350,411), 0.17 g of Aliquat 336.RTM.
(methyltrioctylammonium chloride), 1.12 ml of acetic acid, 56 ml of
dichloromethane, 3.2 ml of sulfuric acid (d=1.84) and 60 ml of
water. Stirring was continued at room temperature for 5 hours. 3.4
g of sodium metabisulfite were added portionwise at
0.degree.-5.degree. C. within 15 minutes. The organic layer was
separated, washed with water and extracted with 60 ml of 1N aqueous
sodium hydroxide solution. The aqueous phase was acidified by
addition of diluted hydrochloric acid and extracted with ethyl
acetate. The organic phase was washed with water, dried on
anhydrous sodium sulfate and, after filtration, evaporated to
dryness in vacuo. The residue was treated with carbon tetrachloride
and the solid was collected by suction to give 1 g of the title
compound, m.p. 191.degree.-192.degree. C. (acetonitrile).
8-(4-Chlorobutyramido)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate XLVIII)
The title compound was prepared in the same manner as Intermediate
X, but using 4-chlorobutyryl chloride instead of acryloyl chloride.
The solid obtained, filtered from water and dried, was rinsed with
hot diethyl ether and collected by suction to give the title
compound. A sample, crystallized from 50% aqueous ethanol and
washed with diethyl ether, melted at (153) 162.degree.-164.degree.
C.
8-Methylamino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (Intermediate
XLIX)
A solution of 0.5 g of Intermediate XXIII in 1.5 ml of anhydrous
dimethylformamide was added dropwise under stirring, at -5.degree.
C. to 0.degree. C., to a suspension of 0.045 g of sodium hydride
(80% in mineral oil). After stirring at room temperature for 1
hour, 0.092 ml of methyl iodide in 0.6 ml of anhydrous
dimethylformamide was added dropwise. Then, the reaction mixture
was stirred at 50.degree. C. for 1 hour, cooled to 20.degree. C.,
poured into water, filtered by suction and dried at 60.degree. C.
for 3 hours to recover 0.6 g of
8-(N-methyltrifluoroacetamido)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.
NMR (CDCl3; (.delta.)) 8.15 (dd, 1H) benzopyran CH in 5 7.10-7.60
(m, 7H) other benzopyran and phenyl CHs 3.30 (s, 3H) CH.sub.3 --N
2.10 (s, 3H) benzopyran CH.sub.3 in 3
A mixture of 0.44 g of the above compound and 0.05 g of sodium
borohydride in 4 ml of ethanol and 1 ml of dimethylsulfoxide was
stirred at room temperature for 1 hour, then quenched with An
excess of 4N aqueous hydrochloric acid solution. After removal of
ethanol by evaporation in vacuo, the residue was rinsed with water,
then with 3N aqueous sodium hydroxide solution and extracted with
ethyl acetate. The organic layer was washed with water, dried on
anhydrous sodium sulfate and evaporated to dryness in vacuo. The
solid residue was crystallized from ethanol to give 0.22 g of the
title compound, melting at 143.degree.-146.degree. C.
8-(N-methylacrylamido)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate L)
This compound was prepared in the same manner as Intermediate X,
but using Intermediate XLIX instead of
8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran. Instead of
diluting with water, THF was removed by evaporation in vacuo and
the crude residue was dissolved in ethyl acetate and washed with
water. The organic solution was dried on anhydrous sodium sulfate
and evaporated to dryness in vacuo to give the title compound. A
sample was purified by column chromatography on silica gel (eluting
with ethyl acetate - petroleum ether (4:6)) and crystallized from
cyclohexane, melted at 136.degree.-137.degree. C.
1-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yloxy)ethyl]-4-(2-methoxyphenyl)p
iperazine (Intermediate LI)
A mixture of 6.73 g of N-hydroxyphthalimide, 3.73 g of sodium
acetate and 10 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine
in 100 ml of anhydrous dimethylsulfoxide was stirred at 100.degree.
C. for 4 hours. The reaction mixture was then cooled to room
temperature, poured into water and extracted with ethyl acetate.
The collected organic layers were washed with 1N aqueous sodium
hydroxide solution, dried on anhydrous sodium sulfate and
evaporated to dryness in vacuo to give 7.58 g of the title
compound. A sample was crystallized from cyclohexane, m.p. (76)
80.degree.-83.degree. C.
1-(2-Aminooxyethyl)-4-(2-methoxyphenyl)piperazine hydrochloride
(Intermediate LII)
A solution of 6.59 g of Intermediate LI and 1.10 ml of 85%
hydrazine hydrate in 130 ml of 95% ethanol was refluxed for 4
hours. Ethanol was removed by evaporation in vacuo. The residue was
rinsed with water then with an excess of 37% hydrochloric acid and
filtered. The aqueous acid solution was made basic with 5% aqueous
sodium hydroxide solution and extracted with chloroform. The
organic layer was dried on anhydrous sodium sulfate and evaporated
to dryness in vacuo to give 4.3 g of the title compound as an oil.
A sample was converted to the hydrochloride by salification with
ethanolic hydrochloric acid in dichoromethane. The solvents were
removed by evaporation in vacuo and the crude residue was
crystallized from ethanol, giving the title compound, m.p.
208.degree.-209.degree. C.
8-(4-Chlorobutylthio)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate LIII)
The title compound was prepared in the same manner as Intermediate
XXXIV, but using 1-bromo-.sub.4 -chlorobutane instead of
1-bromo-3-chloropropane. m.p. 81.degree.-84.degree. C.
(ethanol).
8-(4-Chlorobutylsulfinyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
(Intermediate LIV)
The title compound was prepared in the same manner as Intermediate
XXVI, but using Intermediate LIII instead of Intermediate XXI. A
sample, crystallized from cyclohexane-benzene (0.5:1), melted at
124.degree.-125.degree. C.
8-Carboxy-4-oxo-3-phenyl-4H-1-benzopyran (Intermediate LV)
A solution of 38.22 g of silver nitrate in 75 ml of water was added
dropwise, under stirring, at 20.degree.-25.degree. C., to a
solution of 22.5 g of 8-formyl-4-oxo-3-phenyl-4H-1-benzopyran
(prepared as described by G. Atassi et al., Eur. J. Med. Chem. -
Chim. Ter. 20, 393 (1985)) in 150 ml of 85% ethanol and 450 ml of
N,N-dimethylformamide. Then, a solution of 32.67 g of 85% potassium
hydroxide in 195 ml of water was added dropwise under stirring at
15.degree.-20.degree. C. After additional stirring at room
temperature, the reaction mixture was filtered by suction; the
mother liquor was acidified with 37% hydrochloric acid and diluted
with 1.2 l of water. Filtration by suction and washing with water
to neutrality gave the title compound as a crude. The crude was
suspended in 150 ml of ethyl acetate and stirred with 444 ml of
0.3M aqueous sodium hydrogen carbonate solution until clear layers
were obtained. The aqueous layer was washed with 75 ml of ethyl
acetate, then made acidic with 37% hydrochloric acid, filtered and
dried at 60.degree.-65.degree. C. to give 19, 12 g of the title
compound that melted at (215) 218.degree. C. A sample, crystallized
from ethanol, showed the same melting point, m.p. (215) 218.degree.
C.
8-Chlorocarbonyl-4-oxo-3-phenyl-4H-1-benzopyran (Intermediate
LVI)
A mixture of 15.97 g of Intermediate LV and 15.6 ml of thionyl
chloride in 75 ml of anhydrous toluene was stirred at
80.degree.-85.degree. C. for 4 hours. After removal of the solvent
under vacuo, the residue was rinsed twice with 20 ml of toluene and
evaporating to dryness in vacuo to give, after drying, 16 g of the
title compound melting at (126) 138.degree.-140.degree. C. which
was used without further purification. m.p. (130)
138.degree.-140.degree. C. (toluene).
8-(N-acetylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
Intermediate LVII
A mixture of 3.5 g of
8-carbamoyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (described in
JP 61-238783, 1986), 4.8 ml of acetic anhydride and 0.25 ml of
sulfuric acid (d=1,098) was stirred at 140.degree. C. for 3
minutes. The reaction was cooled to ambient temperature, diluted
with water and filtered by suction to give, after washing with
water and desiccation, 3.88 g of the title compound.
.sup.1 H-NMR (CDCl.sub.3 ; .delta.): 10.50 bs, 1H imidic NH
8.35-8.70 m, 2H CH in position 5 and 7 of the benzopyran ring
7.45-8.00 m, 6H other aromatic CHs 2.60 s, 3H CH.sub.3 CO 2.20 s,
3H CH.sub.3 in position 3 of the benzopyran ring
2-(2-Methylthiophenoxy) acetaldehyde diethyl acetal Intermediate
LVIII
A mixture of 15.2 ml of 97% 2-bromoacetaldehyde diethyl acetal, 14
g of 2-(methylthio)phenol, 13.7 g of anhydrous potassium carbonate
and 3.13 g of tricaprylmethylammonium chloride in 140 ml of
anhydrous dimethylformamide was stirred at 95.degree. C. for 38
hours.
After this period, the reaction mixture was cooled to room
temperature, poured into 1 liter of water and extracted with
diethyl ether; the organic layer was washed with water, dried on
sodium sulfate and evaporated to dryness in vacuo. The oily residue
was purified by column chromatography on silica gel eluting with
petroleum ether-ethyl acetate (99:1). Evaporation in vacuo of the
collected fractions yielded 12.9 g of pure title compound. A sample
was crystallized from n-hexane and melted at 50.degree.-52.degree.
C.
2-(2-Methylthiophenoxy)acetaldehyde Intermediate LIX
A mixture of 10.5 g of Intermediate LVIII and 140 ml of 2N
hydrochloric acid in 85 ml of anhydrous tetrahydrofuran was stirred
at 50.degree. C. for 2 hours. After this period, the organic
solvent was evaporated in vacuo and the aqueous residue was
extracted with ethyl acetate.
The organic layer was washed with water, dried on sodium sulfate
and evaporated to dryness in vacuo giving 9.5 g of the title
compound as a solid which was used without further purification. A
sample was crystallized from cyclohexane yielding the pure title
compound, m.p. 102.degree.-104.degree. C.
8-(4-Chlorobutylsulfonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
Intermediate LX
The title compound was prepared by the same method as Intermediate
XXV, but using Intermediate LIII instead of Intermediate XXI. It
was crystallized from diisopropyl ether and melted at
112.degree.-115.degree. C.
Ethyl 4-oxo-4H-1-benzopyran-8-carboxylate Intermediate LXI
4.35 g of sodium metal was added in pieces at room temperature to a
solution of 9.85 g of ethyl 3-acetyl-2-hydroxy benzoate
(synthesized from 3-acetyl-2-hydroxybenzoic acid (prepared as
described in R. E. Ford, J. Med. Chem., 29, 538 (1986)) refluxing
in 6N ethanolic hydrogen chloride for 1.5 hours, evaporating to
dryness in vacuo and purifying the crude by column chromatography
on silica gel (eluant ethyl acetate-petroleum ether 8:2)--m.p.
47.degree. C. (hexane)) in 98 ml of ethyl formate.
The reaction mixture went spontaneously to reflux for 20 minutes;
then it was stirred at room temperature for 4 hours and ethyl
formate removed by evaporation to dryness in vacuo. The crude solid
obtained was rinsed with 120 ml of ethanol and 67 ml of 5.6M
ethanolic hydrogen chloride. The mixture was stirred at reflux for
30 minutes; after this period it was cooled to room temperature and
evaporated to dryness in vacuo. The residue was purified by column
chromatography on silica gel eluting with a ethyl acetate-petroleum
ether gradient (3:7 to 6:4) to give 8.31 g of the title
compound.
A sample crystallized from cyclohexane melted at
88.degree.-89.degree. C.
4-Oxo-4H-1-benzopyran-8-carboxylic acid Intermediate LXII
30 ml of 6N hydrochloric acid was added to a solution of 4.0 g of
Intermediate LXI in 30 ml of dioxane and the resulting mixture was
stirred at reflux for 5 hours.
After this period, the reaction mixture was cooled at room
temperature and poured into 200 ml of water. After 12 hours at
0.degree.-5.degree. C., the title compound was filtered by suction
and washed with water and diethyl ether yielding, after
desiccation, 2.8 g of the title compound, used without further
purification. A sample washed with boiling acetonitrile-methanol
(25:1), filtered and crystallized from acetic acid melted at
253.degree.-254.degree. C.
6-Hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
Intermediate LXIII
A mixture of 1.5 g of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
(prepared as described in JP 61-15880) and 28 ml of 57% hydroiodic
acid in 47 ml of acetic acid was stirred at reflux for 18 hours.
The reaction mixture was cooled to room temperature and poured into
water; the pH of the suspension was corrected to 4-5 by adding 1N
aqueous sodium hydroxide solution. 2 g of sodium thiosulfate was
added and stirring was continued for 15 minutes. After this period,
the crude title compound was filtered by suction and dissolved in
0.5M aqueous sodium hydroxide solution; the basic solution was
washed with ethyl acetate and acidified to pH=1 by adding 37%
hydrochloric acid.
The title compound was collected by suction and desiccated to give
1.12 g of the title compound, used without further purification and
melting at 279.degree.-281.degree. C. after crystallization from
50% ethanol.
2-Hydroxy-5-nitro-3-propionyl benzoic acid Intermediate LXIV
97.1 g of 2-hydroxy-3-propionyl benzoic acid (prepared as described
in Brit 1, 343, 119 (1974)) were added in 5 minutes to 500 ml of
sulfuric acid d=1.84 stirred at -25.degree. C. A mixture of 40 ml
of 65% nitric acid and 100 ml of sulfuric acid (d=1.84) was added
in 40 minutes maintaining the temperature of the reaction mixture
between -20.degree. and -13.degree. C. The mixture was stirred at
-18.degree. C. for additional 30 minutes. After this period, it was
cautiously poured into a mixture of 2.0 kg of crushed ice and 500
ml of water, stirred for 10 minutes and filtered to give the title
compound, after washing with water and drying at 50.degree. C. for
6 hours. Crystallization of this solid from 50% aqueous ethyl
alcohol solution yielded 91.5 g of title compound melting at
186.degree.-189.degree. C., used without further purification. A
sample was recrystallized from 50% ethyl alcohol and melted at
189.degree.-191.degree. C.
Ethyl 2-hydroxy-5-nitro-3-propionyl benzoate Intermediate LXV
A solution of 93.3 g of Intermediate LXIV and 25 ml of sulfuric
acid (d=1.84) in 490 ml of ethyl alcohol was refluxed for 17
hours.
After cooling to room temperature, 47.7 g of sodium carbonate was
added portionwise and the ethyl alcohol was evaporated in vacuo.
The residue was rinsed with 1.2 liter of water, made alkaline by
adding 37% aqueous sodium hydroxide solution and stirred for 15
minutes. 37% hydrochloric acid was added to this suspension
reaching pH=6. Filtration yielded 85.4 g of the title compound used
without further purification (m.p. 75.degree.-77.degree. C.). A
sample was crystallized twice from ethanol and melted at
76.degree.-77.degree. C.
Ethyl 3-methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate
Intermediate LXVI
A mixture of 48.1 g of Intermediate LXV, 63 ml of benzoyl chloride
and 85.6 g of sodium benzoate was stirred at 180.degree. C. (bath
temperature) for 8 hours.
The pasty mixture was cooled to 60.degree.-70.degree. C.; 700 ml of
50% aqueous ethanol solution was added and the resulting mixture
was stirred again at 50.degree. C. for 30 minutes.
60 ml of 35% aqueous sodium hydroxide solution was added at
5.degree. C. avoiding to exceed 15.degree. C. Filtration by
suction, followed by washing with 50% aqueous ethanol solution and
water afforded a crude product, which was purified by double
passage on column chromatography on silica gel eluting firstly with
a dichloromethane-petroleum ether gradient (8:2 to 9:1) and then
with dichloromethane followed by dichloromethane-ethyl acetate
(95:5). Evaporation in vacuo of the collected fractions gave the
title compound, washed with 140 ml of ethanol to give 43 g, melting
at 132.degree.-133.degree. C. (ethanol).
3-Methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
Intermediate LXVII
A mixture of 15.9 g of Intermediate LXVI and 48 ml of 1N sodium
hydroxide in 320 ml of ethanol was stirred at reflux for 30
minutes. The organic solvent was removed by evaporation in vacuo
and the resulting suspension was diluted with 200 ml of water and
made acidic with 37% hydrochloric acid.
Filtration and washing with diethyl ether yielded 11.1 g of the
title compound melting at (258) 286.degree.-292.degree. C. and used
without further purification. After crystallization from
dimethylformamide-water (6:4), the title compound exhibited the
same melting point.
3-Methyl-6-nitro-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride
Intermediate LXVIII
A mixture of 6.2 g of Intermediate LVII, 5.2 ml of thionyl
chloride, 0.1 ml of anhydrous dimethylformamide in 60 ml of toluene
was stirred at 90.degree. C. for 2 hours. Evaporation in vacuo to
dryness and desiccation yielded 6.5 g of the title compound,
melting at 161.degree.-162.degree. C., which was used without
further purification. A sample was crystallized from toluene and
had the same melting point.
7-Methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
Intermediate LXIX
216 ml of a 0.3M solution of potassium permanganate in water was
added dropwise in 40 minutes into a mixture of 7.94 g of
7-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxaldehyde
(prepared as described in Da Re et al., J. Org. Chem., 25, 1097,
(1960)) and 54 ml of 5% aqueous sodium dihydrogen phosphate
solution in 162 ml of tert-butanol, stirred at 75.degree. C. After
additional 2.5 hours stirring at the same temperature, the reaction
mixture was cooled to room temperature and 81 ml of 1M aqueous
sodium dithionite solution was dropped slowly therein. The mixture
was extracted with ethyl acetate; the organic layer was washed four
times with 160 ml of 0.5N aqueous sodium hydroxide solution. The
collected basic aqueous layers were washed with diethyl ether and
made acidic with 37% hydrochloric acid.
The title compound, that precipitated, was filtered and washed with
water, yielding after desiccation, 3.3 g used in the following step
without further purification and melting at 180.degree.-181.degree.
C. after crystallization from 95% ethanol.
Ethyl 3-propionyl-2-(4-trifluoromethylbenzoyloxy)benzoate
Intermediate LXX
A solution of 6.7 g of 4-trifluoromethylbenzoyl chloride (prepared
from the corresponding benzoic acid and thionyl chloride in benzene
at reflux and used as a crude) in 50 ml of chloroform was added
dropwise to a solution of 7.13 g of ethyl
2-hydroxy-3-propionylbenzoate and 4.9 ml of triethylamine in 50 ml
of chloroform.
The mixture was stirred at room temperature for 2 hours; the
solvent was removed by evaporation in vacuo and the residue was
purified by column chromatography on silica gel eluting with
petroleum ether-ethyl acetate (85:15). Evaporation in vacuo to
dryness of the collected fractions yielded 7.4 g of the title
compound as on oil.
NMR spectrum at 60 MHz ( CDCl.sub.3, (.delta.)) 7.6-8.5 (m, 6H)
aromatic CHs 7.5 (t,1H) phenol ring, CH in 5 4.2 (q,2H )
COOCH.sub.2 2.9 (q,2H) COCH.sub.2 1-1.3 (2t, 6H)
2.times.CH.sub.3
Ethyl
3-methyl-4-oxo-2-(4-trifluoromethylphenyl)-4H-1-benzopyran-8-carboxylate
Intermediate LXXI
A mixture of 6.96 g of Intermediate LXX and 2.58 g of potassium
tert-butoxide in 35 ml of pyridine was stirred at 100.degree. C.
for 2 hours.
After this period, the reaction mixture was cooled to room
temperature, poured into a solution of 50 ml of acetic acid in 600
ml of water and extracted with ethyl acetate. The organic layer was
washed with 10% aqueous hydrochloric acid solution and with water,
dried on sodium sulfate and evaporated to dryness in vacuo to give
6.9 g of
1-(2-hydroxy-3-ethoxycarbonyl)-2-methyl-3-(4-trifluoromethylphenyl)-1,3-pr
opanedione.
A solution of the above Intermediate and 2.2 ml of 37% hydrochloric
acid in 35 ml of glacial acetic acid was stirred at 100.degree. C.
for 1.5 hours.
After cooling to room temperature, the mixture was poured into 630
ml of 1N sodium hydroxide and extracted with ethyl acetate. The
organic layer was washed with water, dried on sodium sulfate and
evaporated to dryness in vacuo. The crude was purified by column
chromatography on silica gel eluting with petroleum ether-ethyl
acetate (85:15). Evaporation in vacuo to dryness yielded 2.95 g of
the title compound, melting at 111.degree.-113.degree. C. after
crystallization from cyclohexane.
3-Methyl-4-oxo-2-(4-trifluoromethylphenyl)-4H-1-benzopyran-8-carboxylic
acid Intermediate LXXII
A mixture of 2.95 g of Intermediate LXXI and 0.43 g of lithium
hydroxide monohydrate in 12.5 ml of methanol and 12.5 ml of
tetrahydrofuran containing 8 ml of water was stirred at room
temperature for 1.5 hours. The mixture was poured into a solution
of 30 ml of 1N aqueous hydrochloric acid solution in 300 ml of
water and filtered by suction to give 2.47 g of the title compound
used without further purification. A sample was crystallized from
60% aqueous ethanol solution and melted at 253.degree.-254.degree.
C.
Ethyl
2-(4-benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate LXXIII
The title compound was synthesized following the procedure of
Intermediate LXX and LXXI in the established order but starting
from 4-benzoylbenzoyl chloride instead of 4-trifluoromethylbenzoyl
chloride and reacting this compound in 1,2-dichloroethane instead
of chloroform in the presence of 4-dimethylaminopyridine instead of
triethylamine.
After the usual workup, the residue was purified by column
chromatography on silica gel eluting with dichloromethane-ethyl
acetate (9:1). Evaporation in vacuo to dryness of the collected
fractions yielded the title compound used without further
purification. A sample was crystallized from cyclohexane and melted
at 125.degree.-136.degree. C. (dec.).
2-(4-Benzoylphenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic
acid Intermediate LXXIV
The title compound was prepared in the same manner as Intermediate
LXXII, but starting from Intermediate LXXIII instead of
Intermediate LXXI. It was purified by dissolving the crude in 0,5M
sodium hydroxide, washing the aqueous layer with ethyl acetate and
precipitating the pure title compound by addition of 37%
hydrochloric acid. A sample was crystallized from acetic acid and
melted at 260.degree.-262.degree. C.
Ethyl 2-(4-phenoxybenzoyloxy)-3-propionylbenzoate Intermediate
LXXV
The title compound was prepared according to the procedure of
Intermediate LXX, but starting from 4-phenoxybenzoyl chloride
instead of 4-trifluoromethylbenzoyl chloride. Evaporation of the
solvent yielded the pure title Compound. NMR spectrum at 200 MHz
(CDCl.sub.3 (.delta.)) 8.17 (dd;3H) phenyl CHs in position or to
the carboxylate groups 7.92 (dd;1H) phenyl CH in position ortho to
the CO group 7.38-7.48 (m;3H) phenyl CHs in position meta to the
carboxylate groups 7.25 (d;1H) CH in position 4 of the phenoxy ring
7.05; 7.10 (2d;4H) other CHs of the phenoxy ring 4.25 (q;2H)
CH.sub.2 O 2.90 (q;2H) CH.sub.2 CO 1.05-1.20 (m;6H)
2.times.CH.sub.3
Ethyl
3-methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran-8-carboxylate
Intermediate LXXVI
The title compound was prepared according to the procedure of
Intermediate LXXI, but starting from Intermediate LXXV instead of
Intermediate LXX. The purification of the crude was performed by
column chromatography on silica gel eluting with petroleum
ether-ethyl acetate (6:4). Evaporation in vacuo yielded the pure
title compound m.p. 98.degree.-100.degree. C.
3-Methyl-4-oxo-2-(4-phenoxyphenyl)-4H-1-benzopyran-8-carboxylic
acid Intermediate LXXVII
The title compound was obtained in the same manner as described for
Intermediate LXXII, but starting from Intermediate LXXVI instead of
Intermediate LXXI (m.p. 216.degree.-218.degree. C.).
2-tert-butyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate LXXVIII
6 ml of pivaloyl chloride was added dropwise into a stirred
solution of 8.9 g of ethyl 2-hydroxy-3-propionylbenzoate in 20 ml
of anhydrous pyridine. The reaction mixture was stirred at
80.degree. C. for 6 hours, cooled at room temperature and poured
into a mixture of 200 g of crushed ice and 30 ml of 10N aqueous
hydrochloric acid solution. After extraction with diethyl ether,
the organic phase was washed with brine, dried on anhydrous sodium
sulfate and evaporated to dryness in vacuo, yielding 11.4 g of
crude ethyl 2-pivaloyloxy-3-propionylbenzoate.
2.4 g of this compound was dissolved in 4 ml of anhydrous pyridine
and added with 1 g of anhydrous potassium tert-butoxide. The
obtained mixture was heated for 15 minutes at 100.degree. C.,
cooled to room temperature and poured into 50 g of iced water
containing 8 ml of 10N aqueous hydrochloric acid solution. After
extraction with diethyl ether, the organic phase was washed with
brine, dried on anhydrous sodium sulfate and evaporated to dryness
in vacuo, yielding 2.1 g of crude ethyl
2-hydroxy-3-(2-pivaloylpropionyl)benzoate, which was used without
purification in the next step.
2 g of this Intermediate was heated at 100.degree. C. for 15
minutes after dissolution in a mixture containing 15 ml of acetic
acid and 1.5 ml of 37% hydrochloric acid. After cooling at room
temperature, the mixture was poured into 100 ml of water and
extracted with diethyl ether. The organic phase was washed with 5%
aqueous sodium hydrogen carbonate solution followed by water, dried
on sodium sulfate and evaporated in vacuo, yielding 1.6 g of crude
ethyl
2-tert-butyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate.
1.5 g of the above ester was dissolved in 20 ml of methanol and
slowly added with 3 ml of 10N aqueous sodium hydroxide solution,
maintaining the temperature between 25.degree. and 35.degree. C.
After 1.5 hours at room temperature, the reaction mixture was
diluted with 100 ml of water and extracted with ethyl acetate. The
aqueous layer was acidified with 3N aqueous hydrochloric acid
solution. The precipitate was collected by suction, washed with
water and crystallized from ethanol, yielding 0.8 g of the title
compound, melting at 225.degree.-228.degree. C.
2-Cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate LXXIX
This compound was prepared according to the reactions sequence and
methods described for Intermediate LXXVIII, but starting from
cyclohexylcarboxylic acid chloride instead of pivaloyl chloride and
with other minor differences. Accordingly, ethyl
2-cyclohexylcarbonyloxy-3-propionylbenzoate was obtained after 8
hrs stirring at room temperature in pyridine and transposed to
1-(3-ethoxycarbonyl-2-hydroxyphenyl)-3-cyclohexyl-2-methyl-1,3-propanedion
e upon heating with potassium tertbutoxide for 2.5 hours at
100.degree. C.
The cyclization of the above Intermediate to ethyl
2-cyclohexyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate was
carried out by heating in the acetic-hydrochloric acids mixture at
100.degree. C. for 1.5 hours and the hydrolysis to the title
compound was performed in 20 minutes at room temperature.
The title compound melted at 224.degree. C. after crystallization
from 40% ethanol.
Ethyl 2-(2-furyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate LXXX
A mixture of 3.2 g of Intermediate XC and 1.3 g of anhydrous
potassium tert-butoxide in 8 ml of anhydrous pyridine was stirred
at 60.degree. C. for 15 minutes, cooled to room temperature and
poured into 60 ml of iced water containing 15 ml of 10N aqueous
hydrochloric acid solution. After extraction with ethyl acetate,
the organic phase was washed with 5% aqueous sodium bicarbonate
solution and water and dried on anhydrous sodium sulfate. Upon
evaporation in vacuo 2.5 g of crude ethyl
3-(2-furoyl)propionyl-2-hydroxybenzoate was obtained.
2.5 g of the above crude was stirred at 100.degree. C. for 30
minutes with 10 ml of acetic acid and 0.7 ml of 37% hydrochloric
acid. After cooling to room temperature, the mixture was poured
into 180 ml of water yielding the title compound as a precipitate,
which was collected by suction, washed with water and crystallized
with i-propanol. 1.5 g were obtained, m.p. 137.degree.-139.degree.
C.
2-(2-Furyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate LXXXI
A mixture of 3.5 g of Intermediate LXXX and 6 ml of 10N sodium
hydroxide in 40 ml of methanol was stirred at room temperature for
1 hour and poured into 500 ml of water. After extraction with ethyl
acetate, the aqueous layer was acidified with 3N hydrochloric acid
and the precipitated title compound was collected by suction,
washed with water and crystallized from a 7:3 mixture of
methanol/chloroform, yielding 2.55 g, m.p. 272.degree.-277.degree.
C.
Ethyl 3-methyl-4-oxo-2-(2-thienyl)-4H-1-benzopyran-8-carboxylate
Intermediate LXXXII
This compound was prepared in two steps according to the method
reported for Intermediate LXXX, but using Intermediate XCI instead
of Intermediate XC. The title compound melted at
116.degree.-118.degree. C. after crystallization from
i-propanol.
3-Methyl-4-oxo-2-(2-thienyl)-4H-1-benzopyran-8-carboxylic acid
Intermediate LXXXIII
This compound was prepared according to the method described for
Intermediate LXXXI, but using Intermediate LXXXII instead of
Intermediate LXXX. Melting point 287.degree.-294.degree. C. after
crystallization from a 7:3 mixture of methanol and chloroform.
4-Oxo-2-phenyl-4H-1-benzothiopyran-8-carboxylic acid Intermediate
LXXXIV
A mixture of 1 g of methyl
4-oxo-2-phenyl-4H-1-benzothiopyran-8-carboxylate (Intermediate
XCII), 2.2 ml of 12.5N sodium hydroxide, 15 ml of methanol and 5 ml
of dioxane was stirred at room temperature for 2.5 hours.
After evaporation in vacuo, water was added until complete solution
and this solution was extracted with chloroform. The separated
aqueous phase was acidified with diluted hydrochloric acid until
Complete precipitation of the crude, that was filtered and purified
by crystallization from acetic acid. Yield 0.62 g, m.p. 302.degree.
C.
(E)-ethyl
3-methyl-4-oxo-2-(2-phenylethenyl)-4H-1-benzopyran-8-carboxylate
Intermediate LXXXV
This compound was prepared in three steps according to the methods
described for Intermediate XC (first step) and Intermediate LXXX
(second and third steps). In the first step, (E)-cinnamoyl chloride
was used instead of 2-furancarbonyl chloride and the obtained
(E)-ethyl 2-hydroxy-3-[2-(2-phenylethenyl)propionyl]benzoate was
used without purification by column chromatography for the second
step. The title compound melted at 129.degree.-130.degree. C. after
crystallization from i-propanol.
(E)-3-methyl-4-oxo-2-(2-phenylethenyl)-4H-1-benzopyran-8-carboxylic
acid Intermediate LXXXVI
This compound was prepared according to the method described for
Intermediate LXXXI, but starting from Intermediate LXXXV instead of
Intermediate LXXX, and maintaining the reaction at room temperature
for 10 hours. The title compound melted at 284.degree.-286.degree.
C. after crystallization from ethanol.
3-Methyl-2-(4-methylphenyl)-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate LXXXVII
A mixture of 1.9 g of 2-hydroxy-3-propionylbenzoic acid (prepared
as described in Brit. 1, 343, 119 (1974)), 5.2 g of anhydrous
sodium 4-methylbenzoate and 3.9 ml of 4-methylbenzoyl chloride was
stirred at 185.degree.-195.degree. C. for 8.5 hours. After cooling
to room temperature, the solidified mass was added with 100 ml of
chloroform and left standing overnight. The mixture was then shaken
with 5% aqueous sodium carbonate solution, which was added until
the pH of the aqueous phase reached pH=8.9. The organic phase was
extracted again with 3% aqueous sodium carbonate solution and the
aqueous phases were pooled, repeatedly extracted with diethyl ether
and acidified with 10N aqueous hydrochloric acid solution. The
precipitate was purified by flash chromatography on silica gel
eluting with a chloroform-methanol gradient (100:2 to 100-20). The
title compound, obtained by evaporating in vacuo the pooled
fractions containing it, melted at 249.degree.-251.degree. C. after
crystallization from ethanol.
Ethyl
2-(4-fluorophenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate LXXXVIII
This compound was prepared in three steps according to the methods
described for Intermediate XC (first step) and Intermediate LXXX
(second and third steps). In the first step, 4-fluorobenzoyl
chloride was used instead of 2-furancarbonyl chloride and the
reaction lasted 20 hours at room temperature, yielding ethyl
2-(4-fluorobenzoyloxy)-3-propionylbenzoate. This compound was used
without purification by column chromatography for the second step.
The title compound melted at 128.degree.-130.degree. C. after
rinsing with diethyl ether and crystallization from ethanol.
2-(4-fluorophenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate LXXXIX
The solution of 3.3 g of Intermediate LXXXVIII and 0.6 g of lithium
hydroxide hydrate in 50 ml of tetrahydrofuran, 10 ml of methanol
and 10 ml of water was maintained at room temperature for 5 hours
and poured into 300 ml of 1N aqueous hydrochloric acid solution.
The precipitate formed was collected by suction, washed with water
and dried, yielding 2.3 g of title compound, melting at
249.degree.-250.degree. C. after crystallization from 95%
ethanol.
Ethyl 2-(2-furylcarbonyloxy)-3-propionylbenzoate Intermediate
XC
4.35 ml of 2-furancarbonyl chloride were added dropwise at
10.degree.-15.degree. C. into a stirred mixture of 8.9 g of ethyl
2-hydroxy-3-propionylbenzoate and 5.4 g of 4-dimethylaminopyridine
in 25 ml of dichloromethane. After 2 hours at room temperature, the
reaction was quenched with 200 ml of water. The organic layer was
washed with 5% sodium bicarbonate, dried on anhydrous sodium
sulfate and evaporated in vacuo. The residue was purified by flash
chromatography on silica gel eluting with petroleum ether-ethyl
acetate 4:1, obtaining 9.4 g of the title compound as a low melting
solid, used without further purification in the next step.
NMR Spectrum at 60 MHz (CDCl.sub.3 ; (.delta.)) 8.2 (1H, dd,
benzoate CH in 4) 8.0 (1H,dd,benzoate CH in 6) 7.7-7.8
(1H,dd,furane CH in 5) 7.43 (1H,t,benzoate CH in 5) 7.45
(1H,s,furane CH in 3) 6.6-6.8 (1H,m,furane CH in 4) 4.3 (2H,
q,COOCH.sub.2 CH.sub.3) 2.9 (2H, q,COCH.sub.2 CH.sub.3) 0.95-1.35
(6H,m,2.times.CH.sub.3)
Ethyl 3-propionyl-2-(2-thienylcarbonyloxy)benzoate Intermediate
XCI
This compound was prepared according to the method of Intermediate
XC, but using 2-thiophenecarbonyl chloride instead of
2-furancarbonyl chloride.
NMR Spectrum at 60 MHz (CDCl.sub.3 (.delta.)) 7.1-8.35
(6H,m,aromatic CHs) 4.25 (2H,q,COOCH.sub.2 CH.sub.3) 2.9
(2H,q,COCH.sub.2 CH.sub.3) 0.95-1.3 (6H,m,2.times.CH.sub.3)
Methyl 4-oxo-2-phenyl-4H-1-benzothiopyran-8-carboxylate
Intermediate XCII
A mixture of 16.8 ml of methyl thiosalicylate, 25.6 ml of ethyl
benzoylacetate and 360 g of polyphosphoric acid was stirred at
90.degree. C. for 3 hours.
After cooling to room temperature, the mixture was poured into
crushed ice and the crude was collected by filtration, washed with
water and purified by crystallization from ethanol (m.p.
170.degree.-171.degree. C.).
Analysis (%) for C.sub.17 H.sub.12 O.sub.3 S, Calcd (Found): C,
68.90 (68.59); H,4.08(4.13); S,10.82(10.69).
NMR spectrum at 200 MHz (CDCl.sub.3, (.delta.)) 8.83-8.95 (dd,1H)
benzothiopyran CH in 5 8.45-8.53 (dd,1H) benzothiopyran CH in 7
7.68-7.80 (m,2H) 2-phenyl CHs in 2 and 6 7.55-7.65 (t,1H)
benzothiopyran CH in 6 7.45-7.55 (m,3H) 2-phenyl CHs in 3,4 and 5
7.24 (s,1H) benzothiopyran CH in 3 4.00 (s,3H) COOCH.sub.3
Ethyl 3-bromomethyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate
Intermediate XCIII
A mixture of 9.2 g of ethyl
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate (prepared as
described by Da Re et al., J. Med. Chem., 2, 263 (1960)), 6.4 g of
N-bromosuccinimide and 0.04 g of benzoylperoxide in 80 ml of
anhydrous carbon tetrachloride was stirred at reflux for 1.5 hours.
After cooling to room temperature the formed succinimide was
collected by suction and washed with cold carbon tetrachloride. The
mother liquors were evaporated to dryness in vacuo and the residue
was rinsed with diethyl ether and collected by suction yielding 9.2
g of the title compound melting at 133.degree.-134.degree. C. after
crystallization from acetone-n-hexane.
Ethyl 3-acetoxymethyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate
Intermediate XCIV
A solution of 10.2 g of sodium acetate. 3H.sub.2 O in 30 ml of
water was added dropwise at room temperature into a solution of 29
g of Intermediate XCIII in 300 ml of dimethylformamide. After
stirring at 50.degree. C. for 1.5 hours, the reaction mixture was
poured into 2 liters of water and the precipitated title compound
was collected by suction and crystallized from acetone yielding 20
g (two crops collected), m.p. 151.degree.-152.degree. C.
3-Hydroxymethyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
Intermediate XCV
116 ml of 1N sodium hydroxide were added over 10 minutes to a
stirred suspension of 14.8 g of Intermediate XCIV in 300 ml of 95%
ethanol. The reaction mixture was then heated at
60.degree.-65.degree. C. for 15 minutes obtaining a clear solution
which was maintained at room temperature for one additional hour.
After evaporation of the solvent in vacuo, the residue was
dissolved in 200 ml of water and the solution acidified by slow
addition of 10 ml of hydrochloric acid (d=1.18). After one hour
stirring at room temperature the title compound was collected by
suction, washed with water and crystallized from i-propanol,
yielding 9.3 g, m.p. (225) 237.degree.-240.degree. C.
Ethyl 2-(4-nitrobenzoyloxy)-3-propionylbenzoate Intermediate
XCVI
The title compound was prepared according to the procedure of
Intermediate XC, but using 4-nitrobenzoylchloride instead of
2-furancarbonyl chloride. The product was obtained as a low-melting
solid (m.p. (40) 78.degree.-80.degree. C.).
NMR Spectrum at 60 MHz (CDCl.sub.3, (.delta.)) 7.85-8.50 (m,6H)
aromatic CHs 7.50 (t,1H) CHs in position 5 of the phenol ring 4.25
(q,2H) CH.sub.2 O 3.95 (q,2H) CH.sub.2 0.95-1.30 (m, 6H)
CH.sub.3
Ethyl
3-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate XCVII
A mixture of 29.7 g of Intermediate XCVI and 10.18 g of anhydrous
potassium tert-butoxide in 89 ml of anhydrous pyridine was stirred
at 100.degree. C. for 13 hours. The reaction mixture was cooled to
room temperature, poured into 400 ml of 4N hydrochloric acid and
extracted with dichloromethane. The organic layer was washed
repeatedly with water, then with 2.5% sodium hydrogen carbonate,
dried on sodium sulfate and evaporated to dryness in vacuo. The
crude was purified by column chromatography on silica gel eluting
with hexane-ethyl acetate (7:3). Evaporation in vacuo of the
collected fraction yielded 7 g of the title compound, melting at
(130) 145.degree.-148.degree. C.
3-methyl-2-(4-nitrophenyl)-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate XCVIII
A suspension of 7.07 g of Intermediate XCVII in 150 ml of dioxane
and 100 ml of methanol was warmed under stirring at 50.degree. C.
22.8 ml of 1N sodium hydroxide was added and stirring was continued
for 0.75 hours at the same temperature. The reaction mixture was
cooled to room temperature and 3N aqueous hydrochloric acid
solution was added reaching pH=1. The suspension was filtered by
suction giving 5.65 g of the title compound, which melted at
320.degree.-321.degree. C. after crystallization from dioxane.
Ethyl
3-methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran-8-carboxylate
Intermediate XCIX
3.16 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise at
0.degree. C. by a syringe to a stirred mixture of 3 g of ethyl
2-hydroxy-3-propionyl benzoate and 5.53 ml of trifluoroacetic
anhydride. The reaction mixture was stirred at 60.degree. C. for 4
hours; after this period it was cooled to room temperature and
diluted with ethyl acetate and water. The organic layer was washed
with 1N sodium hydroxide and water, dried on sodium sulphate and
evaporated to dryness in vacuo. The residue was purified by column
chromatography on silica gel eluting with petroleum ether-ethyl
acetate 95:5 yielding 0.8 g of the title compound. NMR spectrum at
200 MHz (CDCl.sub.3 ; (.delta.)) 8.41;8.37 (2dd;2H) CHs in position
5 and 7 of the benzopyran ring 7.51 (t;1H) CH in position 6 of the
benzopyran ring 4.46 (q;2H) COOCH.sub.2 2.22-2.27 (m;3H,JH-F=2.16
Hz) CH.sub.3 in position 3 of the benzopyran ring 1.39 (t;3H )
CH.sub.2 CH.sub.3
3-Methyl-4-oxo-2-trifluoromethyl-4H-1-benzopyran-8-carboxylic acid
Intermediate C
The title compound was prepared by the same method as Intermediate
LXII, but using Intermediate XCIX instead of Intermediate LXI and,
after dilution with water, extracting with ethyl acetate instead of
filtering.
After drying on sodium sulfate and evaporating in vacuo to dryness
the organic layer, the title compound was obtained as a solid which
melted at 175.degree.-178.degree. C.
3-[4-(2-Methoxyphenyl)-1-piperazinyl]-N-methylpropylamine
Intermediate CI
A solution of 8.2 g of 3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl
chloride in 48 ml of dimethylformamide was added with 42 ml of 35%
aqueous methylamine solution and heated at 60.degree. C. in a
closed vessel for 5 hours. After cooling to 30.degree. C. and
evaporation in vacuo, the residue was stirred for 30 minutes with
100 ml of diethyl ether and collected by suction. The obtained
solid was dissolved in 200 ml of chloroform-5N methanolic ammonia
100:3. After 30 minutes stirring at room temperature, the obtained
solution was adsorbed on a silica gel chromatographic column, which
was eluted with a chloroform-5N methanolic ammonia gradient (100:5
to 100:15). The fractions containing the title compound were pooled
and evaporated in vacuo, yielding 3 g of Intermediate CI as a thick
oil.
NMR spectrum at 60 MHz (DMSO-d.sub.6 (.delta.)) 6.80 (s,4H)
aromatic CHs 3.75 (s,3H) OCH.sub.3 3.20-2.75 (m,4H) piperazinic
CH.sub.2 s at pos. 3,5 2.75-2.10 (m,8H) piperazinic CH.sub.2 S at
pos. 2,6 and CH.sub.2 CH.sub.2 CH.sub.2 2.40 (s,1H) NH 2.30 (s,3H )
NCH.sub.3 1.80-1.40 (m,2H) CH.sub.2 CH.sub.2 CH.sub.2)
Ethyl 2-benzoyl-3-ethylbenzo[b]furan-7-carboxylate Intermediate
CII
A mixture of 11.1 g of ethyl 2-hydroxy-3-propionylbenzoate, 9.9 g
of phenacyl bromide, 6.9 g of anhydrous potassium carbonate and 200
ml of acetone was stirred at refluxing temperature for 7 hours.
After cooling to room temperature, the inorganic salts were
separated by filtration and the solution was evaporated in vacuo.
The residue was purified by flash chromatography on silica gel
eluting with toluene. The title compound, obtained by evaporating
in vacuo the pooled fractions containing it, was crystallized from
90% ethanol. Yield 9.8 g, m.p. 64.degree.-66.degree. C.
2-Benzoyl-3-ethylbenzo[b]furan-7-carboxylic acid Intermediate
CIII
A mixture of 7 g of Intermediate CII, 275 ml of 0.95N sodium
hydroxide and 400 ml of dioxane was stirred at refluxing
temperature for 4 hours. After cooling to room temperature, the
dioxane was evaporated in vacuo and replaced with the same volume
of water. After filtering with charcoal, the solution was acidified
with diluted hydrochloric acid and the precipitate was filtered and
purified by crystallization from acetone, Yield 4.94 g, m.p.
193.degree.-195.degree. C.
Methyl
3-methyl-2-(4-methylphenyl)-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CIV
This compound was prepared in three steps according to the methods
described for Intermediate XC (first step) and Intermediate LXXX
(second and third steps). In the first step, 4-methylbenzoyl
chloride was used instead of 2-furanecarbonyl chloride and methyl
2-hydroxy-3-propionylbenzoate was used instead of ethyl
2-hydroxy-3-propionylbenzoate. The reaction lasted 4 hours at room
temperature, yielding methyl
2-(4-methylbenzoyloxy)3-propionylbenzoate. This compound was used
without purification by column chromatography for the second step,
that lasted 1.5 hours at 100.degree. C. In the third step, 96%
sulfuric acid was used instead of 37% hydrochloric acid. The title
compound melted at 174.degree.-175.degree. C. after crystallization
from ethanol.
Ethyl 2-(4-biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CV
This compound was prepared in three steps according to the methods
described for Intermediate XC (first step) and Intermediate CIV
(second and third steps). In the first step, 4-phenylbenzoyl
chloride was used instead of 2-furanecarbonyl chloride and the
reaction lasted 20 hours at room temperature and 13 hours at
reflux. Purification was performed by column chromatography on
silica gel eluting with a petroleum ether-ethyl acetate gradient
(100:5 to 100:10), yielding ethyl
2-(4-biphenyl-yl)-3-propionylbenzoate. The title compound melted at
165.degree.-167.degree. C. after rinsing with 95% ethanol.
2-(4-Biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CVI
A mixture of 4.3 g of Intermediate CV and 35 ml of 35% hydrochloric
acid in 50 ml of 1,4-dioxane and 15 ml of water was stirred at
reflux for 16 hours. After cooling, the mixture was poured into 200
ml of water and extracted with ethyl acetate. The organic layer was
separated and extracted with 20% aqueous sodium carbonate solution.
The precipitate formed after acidifying the aqueous layer with
diluted hydrochloric acid, was collected by suction, washed with
water and dried, yielding 2.5 g of the title compound, melting at
242.5.degree.-244.degree. C.
2-(4-Hydroxyphenyl)-3-methyl-4-oxo-4H-1benzopyran-8-carboxylic acid
Intermediate CVII
A mixture of 3 g of ethyl
2-(4-methoxyphenyl)3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
(prepared as described in JP 58,225,083; C.A. 100, 191648h (1984))
and 60 ml of 48% hydrobromic acid in 80 ml of acetic acid was
stirred at reflux for 8 hours. After cooling, the mixture was
poured into 500 ml of water and the precipitate was collected by
suction and washed with water. The crude was purified by flash
chromatography eluting with a chloroform-isopropyl alcohol gradient
(9:1 to 7:3) followed by methanol elution, yielding 1 g the title
compound, melting at 300.degree. C.
1-(2-Methoxyphenyl)-4-(4-methylaminobutyl)piperazine Intermediate
CVIII
A solution of 3.8 ml of trifluoroacetic anhydride in 25 ml of
anhydrous dichloromethane was added dropwise under stirring at
0.degree. C. to a solution of 2.53 g of
4-[4-2-methoxyphenyl)-1-piperazinyl]butylamine in 25 ml of
anhydrous dichloromethane. After 2 hours stirring at room
temperature, the reaction mixture was diluted with dichloromethane
and washed with water. The organic layer was dried on sodium
sulphate and evaporated to dryness in vacuo, yielding 3.3 g of pure
1-(2-methoxyphenyl)-4-(4-trifluoroacetylamino)butylpiperazine as by
NMR spectrum.
NMR spectrum at 60 MHz (CDCl.sub.3 (.delta.)) 7.70-8.00 (bs, 1H) NH
6.80-7.20 (m, 4H) aromatic CHs 3.85 (s, 3H) CH.sub.3 O 2.90-3.80
(m, 12H) piperazine CH.sub.2 S, CH.sub.2 N and CH.sub.2 NHCO
1.50-2.05 (m, 4H) C-CH.sub.2 CH.sub.2 -C.
0.88 g of 50% sodium hydride was added portionwise under stirring
at 0.degree. C. to solution of 3.3 g of the above intermediate in
46 ml of anhydrous dimethylformamide. After stirring for one hour
at the same temperature, 0.57 ml of methyl iodide was added.
The reaction mixture was stirred for an additional 1.5 hours and
was then poured into water and extracted with ethyl acetate. The
organic layer was washed with water, dried on sodium sulphate and
evaporated to dryness in vacuo, yielding 1.13 g of crude
1-(2-methoxyphenyl)-4-[4-(N-methyltrifluoroacetylamino)butyl]piperazine,
which was used in the following step without further purification.
0.18 g of sodium borohydride was added to a solution of 1.13 g of
the intermediate in 30 ml of ethanol and the resulting mixture was
stirred at 60.degree. C. for 1 hour,
After cooling to room temperature, the reaction mixture was poured
into water, and extracted with dichloromethane. The organic layer
was washed with water, dried on sodium sulfate and evaporated to
dryness in vacuo, yielding 0.82 g of pure title compound.
NMR spectrum at 60 MHz (CDCl3, (.delta.)) 6.80-7.20 (m, 4H)
aromatic CHs 3.85 (s, 3H) CH.sub.3 O 2.90-3.20 (m, 4H) piperazine
CH.sub.2 S, position 3 and 5 2.30-2.80 (m, 8H) piperazine CH.sub.2
S, position 2 and 6; 2.times.CH.sub.2 N 2.50 (s, 3H) CH.sub.3 N
1.80 (s, 1H) NH 1.40-1.80 (m, 4H) C-CH.sub.2 -CH.sub.2 -C
(E,Z)-3-hydroxy-4-oxo-2-phenyl-8-(1-Propenyl)-4H-1-benzopyran
Intermediate CIX
60 ml of 50% (w/v) sodium hydroxide was added dropwise during 30
minutes to a solution of 17.6 g of a 7:3 E-Z mixture of
2'hydroxy-3'-(1-propenyl)propiophenone (prepared as described in R.
E. Ford. et al., J. Med. Chem., 29, 538, (1986)) and 10.82 g of
benzaldehyde in 73 ml of ethanol stirred at 0.degree. C. The
temperature of the reaction mixture was raised to 25.degree. C. and
stirring was continued for 4 hours. After standing at room
temperature overnight, 150 ml of water was added, followed by
dropwise addition of 95 ml of 37% hydrochloric acid under stirring
at 0.degree. C. The precipitated solid was filtered by suction,
washed with water and desiccated, yielding 26.8 g of
1-[2-hydroxy-3-(1-propenyl)phenyl]-3-phenyl-2-propen-1-one. This
material was used without further purification in the next
step.
26.4 g of the above Intermediate was suspended in 470 ml of
ethanol. The suspension was warmed to reflux till complete
dissolution was reached. The oil bath was then removed and 366 ml
of 10% (w/v) sodium hydroxide was quickly added, dropwise, at
50.degree. C. into the solution, followed by addition of 15.5 ml of
35% hydrogen peroxide. After the reaction mixture reached room
temperature, it was stirred for an additional 15 hours. Thereafter,
the solution was diluted with water and acidified by adding at
0.degree. C. 37% hydrochloric acid. The suspension was filtered by
suction and the obtained solid was washed with water.
This crude material was purified by flash chromatography on silica
gel eluting with dichloromethane. Evaporation in vacuo of the
collected fractions, yielded 6.9 g of the title product, m.p.
165.degree.-168.degree. C., with the same E,Z diastereomeric
composition as the starting compound.
(E,Z)-3-benzyloxy-4-oxo-2-phenyl-8-(1-propenyl)-4H-1-benzopyran
Intermediate CX
A mixture of 2.22 g of Intermediate CIX, 0.2 g of
benzyltriethylammonium chloride, 1.13 ml of 95% benzyl bromide, 11
ml of 50% (w/v) sodium hydroxide in 22 ml of toluene was stirred at
80.degree. C. for 1 hour. The reaction mixture was cooled to room
temperature and extracted with ethyl acetate. The organic layer was
washed with water, dried on sodium sulfate and evaporated to
dryness in vacuo. The crude was rinsed with petroleum ether and
filtered by suction, yielding 1.72 g of the title compound as a 3:1
E-Z mixture, as determined by .sup.1 H-NMR spectrum at 200 MHz. It
melted at 90.degree.-98.degree. C.
NMR spectrum at 200 MHz (CDCl.sub.3 ; (.delta.)) 8.22 (0.25H, dd,
CH in 5 of benzopyran ring; Z isomer) 8.18 (0.75H, dd, CH in 5 of
benzopyran ring; E isomer) 7.95-8.10 (2H, m, CH.sub.S in 2,6 of
2-phenyl ring; Z+E isomers) 7.77 (0.75H, dd, CH in 7 of benzopyran
ring; E isomer) 7.60 (0.25H, dd, CH in 7 of benzopyran ring; Z
isomer) 7.43-7.55 (3H, m, CH.sub.S in 3,4,5 of 2-phenyl ring; E+Z
isomers) 7.20-7.40 (6H, m, CH in 6 of benzopyran ring and CH.sub.S
of benzyl ring; E+Z isomers) 6.91 (0.75H, dd, aryl--CH.dbd., E
isomer) 6.75 (0.25H, dd, aryl--CH.dbd., Z isomer) 6.42 (0.75H, dq,
CH-CH.sub.3, E isomer) 6.05 (0.25H, dq, CH-CH.sub.3, Z isomer) 5.13
(1H, s, CH.sub.2, E+Z isomers) 1.98 (2.25H, dd, CH.sub.3, E isomer)
1.87 (0.75H, dd, CH.sub.3, Z isomer)
After crystallization from methanol, the pure E diastereoisomer
(NMR) was obtained, melting at 98.degree.-100.degree. C.
3-Benzyloxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
Intermediate CXI
4.1 ml of 70% aqueous sulfuric acid solution was added dropwise at
0.degree./5.degree. C. to a stirred mixture of 1.62 g of
Intermediate CX and 3.3 ml of 70% aqueous sodium dichromate
solution in 44 ml of acetone. After the addition, the temperature
was raised to room temperature and stirring was continued for 5.5
hours. 50 ml of cold water was added, followed by a 10% sodium
bisulfite solution to destroy excess oxidizing agent. The mixture
was then extracted three times with ethyl acetate. The combined
ethyl acetate layers were extracted with 0.2N aqueous sodium
hydroxide solution and the aqueous alkaline layer was separated,
washed with diethyl ether and acidified (pH=1) with 37%
hydrochloric acid. The obtained suspension was filtered to give,
after desiccation, 0.62 g of the title compound, m.p.
171.degree.-173.degree. C. After crystallization from acetonitrile,
the compound melted at 175.degree.-176.degree. C.
Ethyl 2-phenyl-4-thioxo-4H-1-benzopyran-8-carboxylate Intermediate
CXII
A solution of 4.0g of
8-ethoxycarbonyl-2-phenyl-4-oxo-4H-1-benzopyran (prepared as
described in Da Re et al., Ber. 1962, 99 (1966)) and 3.55 g of
2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane (Lawesson's
reagent) in 68 ml of toluene was stirred at reflux for 2 hours. The
reaction mixture was cooled to room temperature and evaporated to
dryness in vacuo. The crude residue was rinsed with petroleum ether
and filtered to give a solid. The material was purified by flash
chromatography on silica gel, eluting with a petroleum ether -
ethyl acetate gradient (9:1 to 7:3). Evaporation in vacuo of the
collected fractions yielded 3.99 g of pure title compound, melting
at 161.degree.-163.degree. C. after recrystallization from
cyclohexane.
2-Phenyl-4-thioxo-4H-1-benzopyran-8-carboxylic acid Intermediate
CXIII
The title compound was obtained according to the procedure
described for Intermediate LXXII, but starting from Intermediate
CXII instead of Intermediate LXXI and stirring for 5 hours instead
of 1.5 hour.
The reaction mixture was poured into water containing an excess of
1N aqueous sodium hydroxide solution. The aqueous solution was
washed with ethyl acetate and acidified with 37% HCl at 0.degree.
C. Suction filtration yielded the title compound.
.sup.1 H-NMR Spectrum at 60 MHz (DMSO-d.sub.6 (.delta.))
12.00-13.00 (br, 1H, COOH) 7.60-8.20 (m, 4H, CH.sub.S in 5, 7 of
benzopyran ring and in 2, 6 of phenyl ring) 7.55 (s, 1H, CH in 3 of
benzopyran ring) 7.20-7.55 (m, 3H, other phenyl CHs) 6.90 (t, 1H,
CH in 6 of benzopyran ring)
2,2-Dimethyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]propionaldehyde
dihydrochloride Intermediate CXIV
A mixture of 3 g of 1-(2-methoxyphenyl)piperazine dihydrochloride,
0.4 g of paraformaldehyde and 1 ml of isobutyraldehyde in 4 ml of
ethanol was stirred at reflux for 1.5 hours. 0.4 g of
paraformaldehyde was added and the mixture was stirred again for
1.5 hour at reflux. After cooling to room temperature, water was
added and the resulting solution was washed twice with diethyl
ether, made alkaline by adding 1N aqueous sodium hydroxide solution
and extracted with diethyl ether. The organic layer was washed with
water, dried on sodium sulfate and evaporated to dryness in vacuo.
The crude was purified by flash chromatography on silica gel
eluting with ethyl acetate. Evaporation in vacuo of the collected
fractions yielded 2.1 g of the pure title compound as a base. 0.5 g
of the base was dissolved in diethyl ether and 3.8N hydrochloric
acid in diethyl ether was added. The title compound was recovered
by suction filtration and melted at 181.degree.-183.degree. C.
Methyl
3-methyl-4-oxo-2-(2-phenylethyl)-4H-1-benzopyran-8-carboxylate
Intermediate CXV
This compound was prepared in three steps according to the method
described for Intermediate XC (first step) and Intermediate LXXX
(second and third steps). In the first step, 3-phenylpropionyl
chloride was used instead of 2-furancarbonyl chloride and methyl
2-hydroxy-3-propionylbenzoate was used instead of the ethyl
homolog, yielding methyl
2-(3-phenylpropionyloxy)-3-propionylbenzoate. This compound was
used without purification for the second step. The title compound
melted at 107.5.degree.-109.degree. C. after crystallization from
ethanol.
3-Methyl-4-oxo-2-(2-phenylethyl)-4H-1-benzopyran-8-carboxylic acid
Intermediate CXVI
This compound was prepared according to the method described for
Intermediate LXXXI, but using Intermediate CXV instead of
Intermediate LXXX. The title compound was filtered by suction and
melted at 181.degree.-183.degree. C. after crystallization from
acetonitrile.
N-succinimido 4-oxo-2-phenyl-4H-1-benzothiopyran-8-carboxylate
Intermediate CXVII
A solution of 2.5 g of N,N'-dicyclohexylcarbodiimide in 35 ml of
anhydrous dimethylformamide was added dropwise over 20 minutes at
room temperature to a stirred mixture of 3.5 g of Intermediate
LXXXIV and 1.4 g of N-hydroxysuccinimide in 70 ml of anhydrous
dimethylformamide under a nitrogen atmosphere. After 4 hours at
room temperature, the mixture was poured into 500 ml of water, the
precipitate was filtered by suction and crystallized from ethanol,
yielding 2.5 g of the title compound at 168.degree.-171.degree.
C.
N-succinimido
2-phenyl-1,1,4-trioxo-4H-1-benzothiopyran-8-carboxylate
Intermediate CXVIII
A mixture of 2 g of the above Intermediate CXVII, 20 ml of acetic
acid and 6.2 ml of 30% (w/v) hydrogen peroxide in water was stirred
at 50.degree. C. for 18 hours. After cooling to room temperature,
the reaction mixture was poured into 100 ml of water and extracted
with chloroform. The organic layer was separated, washed with 5%
aqueous sodium hydrogen carbonate solution then with water and
finally dried over anhydrous sodium sulfate. The solvent was
evaporated to dryness in vacuo and the residue was crystallized
from acetone, yielding 0.62 g of the title compound melting at
234.5.degree.-238.degree. C.
Ethyl
2-(4-cyanophenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CXIX
A solution of 5.2 g of ethyl 2-hydroxy-3-propionylbenzoate in 30 ml
of anhydrous pyridine was added dropwise over 20 minutes at room
temperature into a stirred mixture of 4 g of 4-cyanobenzoyl
chloride in 30 ml of anhydrous pyridine. The solution was stirred
for 1 hour at the same temperature, then 2.6 ml of
1,8-diazabicyclo[5.4.0]undec-7-ene was added and the solution was
heated at 100.degree. C. for 2 hours. After cooling to room
temperature, the solvent was evaporated in vacuo and the residue
was quenched with 100 ml of water containing 40 ml of 6N aqueous
hydrochloric acid solution. The mixture was extracted twice with
100 ml aliquots of dichloromethane, the organic layer was
separated, washed with water, dried over sodium sulfate and
evaporated in vacuo. The residue was purified by flash
chromatography on silica gel eluting with n-hexane-ethyl acetate
gradient (95:5 to 60:40), obtaining 3 g of the title compound after
crystallization from ethanol, m.p. 181.degree.-183.degree. C.
4-Cyanophenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CXX
The title compound was prepared according to the method described
for Intermediate XCVIII, but using Intermediate CXIX instead of
Intermediate XCVII. The reaction lasted 45 minutes and the crude
was purified by crystallization from methanol, m.p.
286.degree.-289.degree. C.
Methyl
6-cyano-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate
Intermediate CXXI
A mixture of 3.73 g of methyl
6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate
(prepared as described in EP 107804), 2.69 g of cuprous cyanide and
30 ml of anhydrous N,N-dimethylformamide was heated at 175.degree.
C. under stirring for 4 hours, under nitrogen atmosphere. After
cooling to room temperature, the mixture was poured into 200 ml of
7% aqueous ammonium hydroxide solution and extracted with
chloroform. The organic layer was washed with water, dried over
anhydrous sodium sulfate and evaporated to dryness in vacuo.
The crude was purified by flash chromatography on silica gel
eluting with dichloromethane-methanol gradient (100:0 to 100:20).
1.9 g of the title compound was obtained, melting at
225.degree.-227.degree. C. after crystallization from methanol.
6-Cyano-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-3-carboxylic acid
Intermediate CXXII
The title compound was prepared according to the method described
for Intermediate XCVIII, but using Intermediate CXXI instead of
Intermediate XCVII. The title compound was obtained after
crystallization from acetonitrile, m.p. 281.degree.-283.degree.
C.
(E)-3-Methoxy-4-oxo-2-phenyl-8-(1-propenyl)-4H-1-benzopyran
Intermediate CXXIII
A mixture of 2.68 g of Intermediate CIX, 1.2 ml of methyl iodide,
0.25 g of benzyltriethylammonium chloride and 40 ml of 25% (w/v)
sodium hydroxide in 80 ml of toluene was stirred at 70.degree. C.
for 13 hours.
After this period, the reaction mixture was cooled to room
temperature and diluted with water and ethyl acetate. The organic
layer was then separated, and the aqueous layer extracted twice
with ethyl acetate. The combined extracts were washed with water,
dried on sodium sulfate and evaporated to dryness in vacuo to give
2.55 g of the title compound as a Z/E mixture with the same
composition as Intermediate CIX, which was used in the next step
without further purification. After washing with methanol,
crystallization from the same solvent yielded the pure title
compound, m.p. 121.degree.-123.degree. C.
3-Methoxy-4-oxo-2-phenyl-4H-1 benzopyran-8-carboxylic acid
Intermediate CXXIV
The title compound was prepared by the same method as described for
Intermediate CXI using Intermediate CXXIII instead of Intermediate
CX. m.p. 216.degree.-200.degree. C.
Methyl 2-benzoyl-3-ethylbenzofuran-7-carboxylate Intermediate
CXXV
The title compound was prepared according to the procedure of
Intermediate CII, starting from methyl
2-hydroxy-3-propionylbenzoate instead of ethyl
2-hydroxy-3-propionylbenzoate and carrying out the reaction for 10
hours instead of 7 hours, m.p. 102.5.degree.-104.5.degree. C.
(ethanol).
2-Benzyl-3-ethylbenzofuran-7-carboxylic acid Intermediate CXXVI
A mixture of 1.3 g of Intermediate CXXV, 26 ml of acetic acid and
0.25 g of 10% palladium on charcoal was hydrogenated at 46 p.s.i.
in a Parr apparatus. After the theoretical consumption of hydrogen,
the catalyst was separated by filtration and the solution was
poured into 100 ml of water and extracted with ethyl acetate. The
organic layer was dried over sodium sulphate and evaporated to
dryness (in vacuo) and the crude product was purified by flash
chromatography on silica gel eluting with n-hexane-ethyl acetate
(9:1). The collected fractions containing the pure compound were
evaporated to dryness (in vacuo) yielding 1.1 g of pure methyl
2-benzyl-3-ethylbenzofuran-7-carboxylate, as by NMR spectrum.
.sup.1 H-NMR spectrum at 60 MHz (CDCl.sub.3, (.delta.)) 1.15 (t,
3H) CH.sub.2 CH.sub.3 2.65 (q, 2H) CH.sub.2 CH.sub.3 3.90 (s, 3H)
OCH.sub.3 4.10 (s, 2H) benzyl CH.sub.2 7.10-7.35 (m, 6H) CHs of
phenyl ring; CH in 5, benzofuran ring 7.55 (dd, 1H) CH in 4,
benzofuran ring 7.80 (dd, 1H) CH in 6, benzofuran ring
A mixture of intermediate, 0.234 g of lithium hydroxide hydrate, 10
ml of methanol, 10 ml of tetrahydrofuran and 1.6 ml of water was
stirred at ambient temperature for 2 hours. After standing
overnight, the mixture was poured into 100 ml of water and
acidified with 3N hydrochloric acid. The precipitate was collected
by suction filtration and washed with water. The yield of pure
title compound was 0.63 g, m.p. 151.degree.-153.degree. C.
Methyl 2-(2-phenyl)benzoyloxy-3-propionylbenzoate Intermediate
CXXVII
To a solution of 5.5 g of methyl 2-hydroxy-3-propionylbenzoate in
15 ml of anhydrous pyridine at room temperature was added 6.85 g of
2-phenylbenzoyl chloride. The mixture was stirred at 100.degree. C.
for 3 hours. After cooling to room temperature, the mixture was
poured into 100 ml of water, acidified with hydrochloric acid and
extracted with ethyl acetate. The organic layer was washed with
dilute hydrochloric acid, water and 5% sodium bicarbonate solution,
dried over anhydrous sodium sulfate and evaporated to dryness (in
vacuo). The crude product was purified by flash chromatography on
silica gel eluting with petroleum ether/ethyl acetate (4:1).
Crystallization from ethanol yielded 7.6 g of the title compound,
m.p. 110.degree.-112.degree. C.
Methyl 2-hydroxy-3-[2-(2-phenyl)benzoyl]propionylbenzoate
Intermediate CXXVIII
A mixture of 8 g of Intermediate CXXVII, 2.62 g of potassium
tert-butoxide and 30 ml of anhydrous pyridine was stirred at
60.degree. C. under nitrogen atmosphere for 3 hours. After cooling,
the mixture was poured into 150 ml of water and acidified by
addition of 15% hydrochloric acid. The crude solid product was
collected by filtration and crystallized from ethanol yielding 5.6
g of the title compound, m.p. 126.degree.-127.degree. C.
Methyl
2-(2-biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CXXIX
A mixture of 6.34 g of Intermediate CXXVIII, 3 ml of 37%
hydrochloric acid and 50 ml of acetic acid was stirred at reflux
temperature for 2.5 hours. After cooling, the mixture was poured
into 200 ml of water. The precipitate was collected by filtration
and crystallized from isopropyl alcohol to provide 3.55 g of the
title compound, m.p. 115.degree.-119.degree. C.
Methyl 2-(3-nitrobenzoyloxy)-3-propionylbenzoate Intermediate
CXXX
The title compound was prepared according to the procedure of
Intermediate CXXVII, starting from 3-nitrobenzoyl chloride instead
of 2-phenylbenzoyl chloride. The reaction lasted 7 hours at room
temperature. The solvent was evaporated (in vacuo) and the residue
was rinsed with water, acidified with 37% hydrochloric acid and
extracted with ethyl acetate. The crude product was obtained by
evaporation (in vacuo) of the organic phase. Crystallization from
ethanol provided the title compound, m.p. 83.degree.-84.degree.
C.
Methyl 2-(1-naphthoyloxy)-3-propionylbenzoate Intermediate
CXXXI
The title compound was prepared according to the procedure of
Intermediate CXXVII, starting from 1-naphthoyl chloride instead of
2-phenylbenzoyl chloride. The reaction lasted 3.5 hours at
60.degree. C. then the mixture was poured into water and extracted
with ethyl acetate. The crude product was purified by
crystallization from ethanol to provide the title compound, m.p.
67.degree.-70.degree. C.
Methyl 3-methyl-2-(1-naphthyl)-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CXXXII
The title compound was prepared according to the procedure of
Intermediate LXXI, using Intermediate CXXXI instead of Intermediate
LXX. The .beta.-diketone intermediate methyl
2-hydroxy-3-[2-(1-naphthyl)carbonyl]propionylbenzoate was
characterized by NMR spectrum as follows.
.sup.1 H-NMR spectrum at 60 MHz (CDCl.sub.3, (.delta.)) 1.45-1.65
(d, 3H) COCH(CH.sub.3) CO 4.00 (s, 3H) OCH.sub.3 5.50-5.95 (q, 1H)
COCH(CH.sub.3) CO 7.00 (t1H, CH in 5, phenyl ring 7.30-8.80 (m, 9H)
all other aromatic CHs 11.00 (s, 1H) OH
The crude product obtained after cyclization was purified by
crystallization from ethanol to provide pure title compound, m.p.
155.degree.-157.degree. C.
3-Hydroxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
Intermediate CXXXIII
A mixture of 1.12 g of Intermediate CXI and 14 ml of 37%
hydrochloric acid (w/w) in 28 ml of glacial acetic acid was stirred
at 60.degree. C. for 2 hours. After this period, the reaction
mixture was cooled to room temperature, diluted with 60 ml of water
and stirred for 1 hour. The solid which precipitated was filtered
and washed with water to neutrality. Desiccation yielded 0.77 g of
the title compound, m.p. 293.degree.-294.degree. C.; (EtOH
95%).
1-(5-Hydroxy-2-methoxyphenyl)piperazine dihydrobromide Intermediate
CXXXIV
A solution of 13 g of 1-(2,5-dimethoxyphenyl)piperazine
dihydrochloride (prepared according to R. A. Lyon et al., J. Med.
Chem. 29, 630-634 (1986)) in 67 ml of 48% hydrobromic acid was
stirred at reflux for 2 hours. After cooling to 5.degree. C., the
reaction mixture was maintained at the same temperature for 12
hours. Afterwards, it was filtered and the mother liquor was
evaporated to dryness (in vacuo). The residue was rinsed with 200
ml of ethanol and stirred at reflux for 30 min. After overnight
cooling at 0.degree. C. 11.48 g of the title compound was recovered
by (in vacuo) filtration, m.p. 270.degree.-272.degree. C. (dec.);
(water).
Ethyl 2-cyclohexyl-3,4-dihydro-2H-1-benzopyran-8-carboxylate
Intermediate CXXXV
A solution of 4.38 g of ethyl
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate, prepared as described
by Da Re et al., Ber. 99, 1962 (1966), in 100 ml of methanol and 50
ml of chloroform was hydrogenated in the presence of 0.88 g of 70%
platinum dioxide at an hydrogen pressure of 20 psi (Parr
apparatus). After 3 hours stirring and standing overnight, the
reaction mixture was degassed and the catalyst filtered off. The
solvents were evaporated under vacuum and the crude product was
purified by flash chromatography (eluant, petroleum ether/ethyl
acetate, 98:2). A yield of 2.4 g of the title compound was obtained
as a low-melting solid.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3 (.delta.)): 7.59 (1H,
dd) CH in 7(5), benzopyran 7.14 (1H, dd) CH in 5(7), benzopyran
6.80 (1H, dd) CH in 6, benzopyran 4.34 (2H, q) CH.sub.2 O 3.70-3.90
(1H, m) CHO 2.70-2.85 (2H, m) CH.sub.2 in 4, benzopyran 1.10-2.20
(13H, m) cyclohexyl CH and CH.sub.2 s; CH.sub.2 in 3, benzopyran
1.37 (3H, t) CH.sub.3 CH.sub.2
2-Cyclohexyl-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid
Intermediate CXXXVI
A mixture of 2.29 g of Intermediate CXXXV, 0.48 g of lithium
hydroxide monohydrate and 6 ml of water in 38 ml of
tetrahydrofuran/methanol (1:1) was stirred for 12 hours at room
temperature. Afterwards, the reaction mixture was poured into 21 ml
of 1N sodium hydroxide. The alkaline aqueous layer was washed with
ethyl acetate, acidified (pH=1) with 1N hydrochloric acid and
extracted with ethyl acetate. Evaporation (in vacuo) yielded 1.89 g
of the title compound, m.p. 78.degree.-88.degree. C.
Ethyl 2-(1-adamantyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CXXXVII
To a solution of 4.35 g of 1-adamantoyl chloride and 3.31 g of
ethyl 2-hydroxy-3-propionylbenzoate in 48 ml of anhydrous pyridine
was added 4.6 g of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction
mixture was stirred at room temperature for 2 hours and at
60.degree.-70.degree. C. for 4 hours. After cooling the reaction
mixture was poured into 6N hydrochloric acid and extracted with
ethyl acetate. The organic layer was washed with water, dried on
sodium sulfate and evaporated to dryness (in vacuo).
The residue was added with 100 ml of glacial acetic acid and 10 ml
of 37% hydrochloric acid and heated at reflux for 3 hours. The
reaction mixture was cooled, poured into 0.1N sodium hydroxide and
filtered by suction. The gummy solid obtained was dissolved in
chloroform, dried on sodium sulfate and evaporated to dryness (in
vacuo). The crude product was purified by flash chromatography
eluting with petroleum ether/ethyl acetate (9:1), yielding 1.64 g
of the title compound, as a low-melting solid.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3 (.delta.)) : 8.37 (1H,
dd) CH in 5(7), benzopyran 8.16 (1H, dd) CH in 7(5), benzopyran
7.39 (1H, dd) CH in 6, benzopyran 4.46 (2H, q) CH.sub.3 CH.sub.2 O
2.30 (3H, s) CH.sub.3 C 2.20-2.26 and 1.90-1.94 (15H, m) adamantane
CHs and CH.sub.2 s 1.43 (3H, t) CH.sub.3 CH.sub.2
2-(1-Adamantyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylicacid
Intermediate CXXXVIII
The title compound was prepared according to the procedure
described for Intermediate LXXXIX starting from Intermediate
CXXXVII instead of Intermediate LXXXVIII.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3, (.delta.)) 9.50-12.00
(1H, bb) COOH 8.47 (1H, dd) CH in 7 (5), benzopyran 8.32 (1H, dd)
CH in 5 (7), benzopyran 7.41 (1H, dd) CH in 6, benzopyran 2.31 (3H,
s) CH.sub.3 2.20-2.30 and 1.90-2.00 (15H, m) adamantane CHs and
CH.sub.2 s
8-(5-Bromopentylthio)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
Intermediate CXXXIX
The title compound was obtained according to the procedure
described for Intermediate XXXIV using 1,5-dibromopentane instead
of 1-chloro-3-bromopropane. The crude product was purified by flash
chromatography by eluting with a petroleum ether-ethyl acetate
mixture (8:2). The residue was crystallized from 2-propanol to
provide the title compound, m.p. 68.degree.-70.degree. C.
8-(5-Bromopentylsulfonyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
Intermediate CXL
The title compound was prepared by the same method as Intermediate
XXXV, using Intermediate CXXXIX instead of Intermediate XXXIV. The
product was crystallized from ethanol, m.p. 94.degree.-96.degree.
C.
3-Ethoxymethyl-2-phenyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CXLI
To a stirred solution of sodium ethoxide, prepared by dissolving
0.23 g of sodium into 20 ml of ethanol, under nitrogen atmosphere
was added 1.94 g of Intermediate XCIII. The mixture was heated at
reflux for 4 hours. After cooling to room temperature the reaction
mixture was diluted with 50 ml of water and the ethanol was
evaporated (in vacuo). The aqueous solution was extracted with
diethyl ether. The extracts were acidified by addition of 37%
hydrochloric acid. The precipitate which formed was collected by
suction, washed with water and crystallized from acetonitrile
yielding 1.15 g of the title compound, m.p. 194.degree.-198.degree.
C.
3-Benzyloxymethyl-2-phenyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CXLII
A mixture of 3.15 ml of benzyl alcohol, 1.25 g of 50% sodium
hydride in mineral oil and 120 ml of tetrahydrofuran was stirred at
reflux temperature under nitrogen atmosphere. After 5 hours, 5.03 g
of Intermediate XCIII and 0.35 g of tetrabutylammonium bromide were
added. Stirring was continued for 12 hours at the reflux
temperature. After cooling to room temperature, the mixture was
poured into 200 ml of water and 37% hydrochloric acid was added
cautiously until the reaction mixture was acidic. The mixture was
extracted with ethyl acetate. The organic layer was washed with
water, dried over sodium sulfate and evaporated to dryness (in
vacuo). Crystallization of the crude product from ethanol provided
2.55 g of the title compound, m.p. 218.degree.-220.degree. C.
3-Methyl-2-(1-naphthyl)-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CXLIII
The title compound was prepared according to the procedure of
Intermediate LXVII, starting from Intermediate CXXXI instead of
Intermediate LXVI and carrying out the reaction at 30.degree. C.
After crystallization from ethanol, the title compound melted at
254.degree.-256.degree. C.
2-(2-Biphenylyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CXLIV
The title compound was prepared according to the procedure of
Intermediate LXVII, starting from Intermediate CXXIX instead of
Intermediate LXVI. The reaction was carried out at 30.degree. C.
After crystallization from isopropanol, the product melted at
245.degree.-250.degree. C.
(Z,E)-8-{4-[2-(1,3-Dioxolanyl)]-1-butenyl}-3-methyl-4-oxo-2-phenyl-4H-1-ben
zopyran Intermediate CXLV
The title compound was prepared according to the procedure
described for Intermediate XLV using 3-[2-(1,3-dioxolanyl)]propyl
triphenylphosphonium iodide (prepared as described by E. Bertele et
al., Helvetica Chimica Acta 50, 2445-2456 (1967)) instead of
2-[2-(1,3-dioxanyl)]ethyl triphenylphosphonium bromide.
Chromatographic purification provided the title compound as a
mixture of E and Z diastereoisomers (oil). The ratio of the two
isomers was determined by NMR spectroscopy. The ratio was
E:Z=6:4.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3 (.delta.)) 8.18; 8.12
(1H; 2dd) benzopyran, CH in 7 (E+Z) 7.55-7.78 (3H; m) benzopyran,
CH in 5; phenyl CHs in 2, 6 7.45-7.55 (3H; m) phenyl CHs in 3, 4, 5
7.37; 7.31 (1H; 2dd) benzopyran, CH in 6 (E+Z) 6.85 (0.6H; d)
Aryl--CH.dbd.(E) 6.70 (0.4H; d) Aryl CH.dbd.(Z) 6.45 (0.6H; dt)
CH.dbd.CH--CH.sub.2 (Z) 5.87 (0.4H; dt) CH.dbd.CHCH.sub.2 (E) 4.92;
4.87 (1H; 2t) dioxolanyl CH(Z+E) 3.75-4.20 (4H; m) dioxolanyl
CH.sub.2 s 2.35-2.50 (2H; m) CH.sub.2 CH 2.19; 2.18 (3H; 2s)
CH.sub.3 (Z+E) 1.75-1.95 (2H; m) CH.sub.2 --CH.dbd.
8-{4-[2-(1,3-Dioxolanyl)]butyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
Intermediate CXLVI
The title compound was prepared following the procedure described
for Intermediate XLVI starting from Intermediate CXLV instead of
Intermediate XLV. Evaporation of the reaction solvent (in vacuo)
provided a white solid, which was crystallized from cyclohexane,
m.p. 69.degree.-71.degree. C.
3-Methyl-4-oxo-8-(5-oxopentyl)-2-phenyl-4H-1-benzopyran
Intermediate CXLVII
The title compound was prepared following the procedure described
for the last step of Intermediate XXXIX starting from Intermediate
CXLVI instead of
2-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}dioxolane. The
compound was obtained as a solid, m.p. 46.degree.-50.degree. C.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3, (.delta.)) : 9.71
(1H; t) CHO 8.15 (1H; dd) benzopyran, CH in 5 7.60-7.75 (2H; m)
phenyl CHs in 2, 6 7.40-7.60 (4H; m) benzopyran CH in 7; phenyl CHs
in 3, 4, 5 7.31 (1H; dd) CH of benzopyran in 6 2.90 (2H; t)
aryl-CH.sub.2 2.35-2.55 (2H; m) CH.sub.2 CHO 2.18 (3H; s) CH.sub.3
1.55-1.85 ( 4H; m) CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2
Ethyl
3-methyl-2-(4-methylcyclohexyl)-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CXLVIII
A mixture of 4.26 g of 4-methylcyclohexanecarboxylic acid, 2.19 ml
of thionyl chloride and 0.16 ml of pyridine in 60 ml of diethyl
ether was stirred at room temperature for 12 hours. Then the
solvent was removed (in vacuo). The crude
4-methylcyclohexanecarbonyl chloride obtained was mixed with 6.17 g
of ethyl 2-hydroxy-3-propionylbenzoate and 9 ml of
1,8-diazabicyclo[5,4,0]-undec-7-ene in 90 ml of pyridine. The
solution was stirred for hours at room temperature and at
70.degree. C. for 6 hours. After cooling to room temperature, the
reaction mixture was poured into water, acidified to pH=1, with 37%
hydrochloric acid and extracted with chloroform. After the usual
workup, the residue was purified by flash chromatography eluting
with petroleum ether/ethyl acetate (9:1) to provide 6.64 g of the
title compound.
.sup.1 H-NMR spectrum at 200 MHz (CDCl3 (.delta.)) : 8.40 (dd, 1H)
benzopyran CH in 7 8.20 (dd, 1H) benzopyran CH in 5 7.38 (dd, 1H)
benzopyran CH in 6 4.46 (q, 2H) CH.sub.2 O 2.75-2.95 (m, 1H) CH-C-O
cyclohexyl C.sub.1 2.10 (s, 3H) benzopyran CH.sub.3 in 3 1.60-1.95
(m, 6H) cyclohexyl protons 1.45-1.60 (m, 1H) CHCH.sub.3 cyclohexyl
C4 1.45 (t, 3H) CH.sub.3 CH.sub.2 1.00-1.20 (m, 2H) cyclohexyl
protons 0.96 (d, 3H) CH.sub.3 CH
3-Methyl-2-(4-methylcyclohexyl)-4-oxo-4H-1-benzopyran-8-carboxylic
acid Intermediate CXLIX
The title compound was prepared as described for Intermediate
CXXXVI starting from Intermediate CXLVIII instead of Intermediate
CXXXV. Evaporation of the solvent (in vacuo) was followed by
dilution with water. Acidification of the solution with 1N
hydrochloric acid provided the pure title compound. This was
collected by filtration, m.p. 220.degree.-224.degree. C.
Ethyl 3-(2-cyclopentylcarbonyl)propionyl-2-hydroxybenzoate
Intermediate CL
This compound was prepared in 2 steps. The first step was carried
out according to the procedure of Intermediate CXXVII starting from
ethyl 2-hydroxy-3-propionylbenzoate instead of methyl
2-hydroxy-3-propionylbenzoate and from cyclopropylcarbonyl chloride
(prepared as described by G. B. Payne et al., J. Org. Chem. 22,
1680 (1957)) instead of 2-phenylbenzoyl chloride. The reaction was
carried for 2 hours at 80.degree. C. After cooling, to room
temperature, the mixture was concentrated (in vacuo) to a small
volume and added to water. The crude methyl
2-cyclopropylcarbonyloxy-3-propionylbenzoate so obtained was used
for the second step without further purification.
The second step was carried out according to the procedure of
Intermediate CXXVIII, using the ester intermediate prepared above
instead of Intermediate CXXVII. After acidification, the mixture
was extracted with ethyl acetate and the organic extracts were
dried over sodium sulfate. The solvent was removed (in vacuo). The
title compound was crystallization from ethanol, m.p.
87.degree.-90.degree. C.
Ethyl
2-cyclopentyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate
Intermediate CLI
This compound was prepared according to the procedure of
Intermediate CXXIX, using Intermediate CL instead of Intermediate
CXXVIII. The reaction was stirred at 100.degree. C. for 15 minutes.
The crude product was purified by flash chromatography on silica
gel eluting with n-hexane/ethyl acetate (4:1). After
crystallization from ethanol, the title compound melted at
79.degree.-80.degree. C.
2-Cyclopentyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CLII
This compound was prepared according to the procedure of
Intermediate LXVII, starting from Intermediate CLI instead of
Intermediate LXVI. The reaction was carried out at room temperature
for 1 hour using methanol as co-solvent, in place of ethanol. The
title compound was crystallized from acetonitrile, m.p.
193.degree.-196.degree. C.
Methyl
2-hydroxy-3-[2-(1-phenylcyclopentyl)carbonyl]propionylbenzoate
Intermediate CLIII
This compound was prepared in 2 steps. The first step was carried
out according to the procedure of Intermediate CXXVII starting from
1-phenylcyclopentylcarbonyl chloride (prepared as described in S.
L. Calderon et al., J. Med. Chem. 34, 3163 (1991)) instead of
2-phenylbenzoyl chloride. The reaction was conducted for 2 hours at
70.degree. C. and 12 hours at room temperature and the mixture was
concentrated (in vacuo) to a small volume before adding to water.
The precipitate was extracted with ethyl acetate. The organic layer
was washed, in succession, with dilute hydrochloric acid, 5% sodium
bicarbonate solution, and water. This was followed by drying over
anhydrous sodium sulfate. The crude methyl
2-(1-phenylcyclopentylcarbonyloxy)-3-propionylbenzoate was obtained
by evaporation of the solvent. The product was used for the second
step without further purification.
The second step was carried out according to the procedure of
Intermediate CXXVIII, using the ester intermediate prepared above
instead of Intermediate CXXVII and 1.1 eq of
1,8-diazabicyclo[5.4.0]undec-7-ene instead of potassium t-butoxide.
The reaction was conducted for 2 hours at 100.degree. C. After
cooling to room temperature, the mixture was concentrated (in
vacuo) to a small volume and added to water. The precipitate was
extracted with ethyl acetate. The organic layer was washed, in
succession, with dilute hydrochloric acid, 5% sodium bicarbonate
solution, and water. This was followed by drying over anhydrous
sodium sulfate. The crude product was purified by flash
chromatography on silica gel, eluting with n-hexane-ethyl acetate
(4:1). Crystallization from ethanol provided the pure title
compound, m.p. 114.degree.-116.degree. C.
Methyl3-methyl-2-(1-phenylcyclopentyl)-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CLIV
This compound was prepared according to the procedure of
Intermediate CXXIX, using Intermediate CLIII instead of
Intermediate CXXVIII and stirring at 100.degree. C. for 4.5 hours.
After crystallization from ethanol, the title compound melted at
95.degree.-97.degree. C.
3-Methyl-2-(1-phenylcyclopentyl)-4-oxo-4H-1-benzopyran-8-carboxylic
acid Intermediate CLV
This compound was prepared according to the procedure of
Intermediate LXVII, starting from Intermediate CLIV instead of
Intermediate LXVI and carrying out the reaction at room temperature
for 10 hours using a mixture of methanol/1,4-dioxane (5:3) instead
of ethanol. After crystallization from ethanol, the title compound
melted at 218.degree.-220.degree. C.
3-Methyl-2-(1-methylcyclohexyl)-4-oxo-4H-1-benzopyran-8-carboxylic
acid Intermediate CLVI
A solution of 6.25 g of methyl 2-hydroxy-3-propionylbenzoate in 15
ml of anhydrous pyridine was prepared and maintained at room
temperature. 1-Methylcyclohexylcarbonyl chloride, 4.85 g, (prepared
as described in Rouzaud J. et al., Bull. Soc. Chim. Fr. 7, 2030
(1965); (Chem. Abst. 63, 11378e (1963)) was added to the solution.
The mixture was stirred at 70.degree. C. for 2 hours, concentrated
to small volume (in vacuo) and poured into water. The precipitate
was extracted with ethyl acetate. The organic layer was washed, in
succession, with dilute hydrochloric acid, 5% sodium bicarbonate
solution and water. This was followed by drying over anhydrous
sodium sulfate. The solvent was evaporated to dryness to give 8.75
g of the crude methyl
2-(1-methylcyclohexylcarbonyloxy)-3-propionylbenzoate This compound
was utilized without further purification.
A mixture of 7.18 g of the ester intermediate prepared above, 5 ml
of 1,8-diazabicyclo[5.4.0]undec-7-ene and 24 ml of anhydrous
pyridine was stirred at 100.degree. C. for 3 hours and then
concentrated to small volume (in vacuo) and poured into water. The
precipitate was extracted with ethyl acetate. The organic layer was
washed, in succession, with dilute hydrochloric acid, 5% sodium
bicarbonate solution and water. This was followed by drying over
anhydrous sodium sulfate. The solvent was evaporated to dryness to
give 6.48 g of methyl
2-hydroxy-3-[2-(1-methylcyclohexylcarbonyl)]propionylbenzoate. This
compound was utilized without further purification.
A mixture of 4.4 g of the methyl benzoate intermediate prepared
above, 0.5 ml of 37% hydrochloric acid and 18 ml of acetic acid was
stirred at 100.degree. C. for 3.5 hours. After cooling, the mixture
was poured into 100 ml of water and the precipitate was extracted
with ethyl acetate. The organic layer was washed with 2N aqueous
sodium hydroxide solution and water, dried over anhydrous sodium
sulfate and evaporated to dryness (in vacuo) to provide 2.89 g of
crude methyl
3-methyl-2-(1-methylcyclohexyl)-4-oxo-4H-1-benzopyran-8-carboxylate.
This compound was used without further purification for the final
step.
The title compound was prepared according to the procedure of the
Intermediate LXVII, starting from 2.42 g of intermediate prepared
above instead of Intermediate LXVI and carrying out the reaction at
room temperature for 5 hours. Crystallization from acetonitrile
provided 1.2 g of the title compound, m.p. 195.degree.-198.degree.
C.
.sup.1 H-NMR spectrum at 200 MHz (DMSO-d.sub.6, (.delta.)) 1.33 (s,
3H) CH.sub.3 in 1, cyclohexane ring 1.20-1.65 (m, 8H) CHs of
cyclohexane ring 2.14 (s, 3H) CH3 in 3, benzopyran ring 2.45-2.60
(m, 2H) CHs of cyclohexane ring 7.50 (dd, 1H) CH in 6, benzopyran
ring 8.10 and 8.25 (2dd, 2H) CHs in 5 and 7, benzopyran ring 13.40
(bs, 1H) COOH
Methyl
2-(bicyclo[2.2.1]hept-5-en-2-yl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxyl
ate Intermediate CLVII
A solution of 12.9 g of bicyclo[2.2.1]hept-5-en-2-carbonyl chloride
(prepared as described in Parham, W. E. et al., J. Am. Chem. Soc.
73, 5068 (1951)) in 20 ml of anhydrous pyridine was added dropwise,
at room temperature, over about 15 minutes, into a stirred solution
of 14.6 g of methyl 2-hydroxy-3-propionylbenzoate in 50 ml of
anhydrous pyridine. After 3 hours stirring and 24 hours standing at
room temperature, 24.5 ml of 1,8-diazabicyclo[5.4.0]-undec-7-ene
was added and stirring was continued for 2 hours at room
temperature followed by 3.5 hours at 80.degree. C. After cooling to
room temperature, the mixture was poured into 500 ml of ice-water,
acidified with 37% hydrochloric acid and extracted with chloroform.
The organic layer was washed with water, dried over anhydrous
sodium sulfate, and evaporated to dryness (in vacuo). The crude
product was purified by flash chromatography on silica gel eluting
with petroleum ether/ethyl acetate (9:1) to provide 11.5 g of the
title compound as on oily mixture (from the NMR spectrum mixture of
endo-exo isomers), m.p. 91.degree.-93.degree. C. (n-hexane).
.sup.1 H-NMR spectrum at 200 MHz (CDCl.sub.3, (.delta.)) 1.35-1.65
(m, 2H) CH.sub.2 in 7 of bicycloheptene ring 1.90-2.25 (m, 2H)
CH.sub.2 in 3 of bicycloheptene ring 2.11 (s, 3H) CH.sub.3 in pos.
3 of benzopyran ring 2.80-3.15 (m, 3H) CHs in 1, 2 and 4 of
bicycloheptene ring 6.10-6.35 (m, 2H) CHs in 5 and 6 of
bicycloheptene ring 7.40 (dd, 1H) CH in 6 of benzopyran ring 8.20
(dd, 1H) CH in 7(5) of benzopyran ring 8.42 (dd, 1H) CH in 5(7) of
benzopyran ring
2-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxyli
c acid Intermediate CLVIII
This compound was prepared according to the procedure of
Intermediate LXVII, starting from Intermediate CLVII instead of
Intermediate LXVI. The reaction was carried out at
50.degree.-55.degree. C. for 3 hours using 1,4-dioxane as the
solvent instead of methanol. The crude product was purified by
flash chromatography on silica gel eluting with chloroform/methanol
(10:1). After crystallization from acetonitrile, the title compound
melted at 199.degree.-200.degree. C. This was a mixture of endo-exo
isomers, determined from the NMR spectrum.
.sup.1 H-NMR spectrum at 200 MHz (CDCl.sub.3, (.delta.)) 1.45-1.70
(m, 2H) bicycloheptene ring, CH.sub.2 in 7 1.90-2.30 (m, 5H)
CH.sub.2 in 3, bicycloheptene ring and CH.sub.3 in 3, benzopyran
ring 2.85-3.75 (m, 3H) CHs in 1,2,4 of bicycloheptene ring
5.80-6.40 (m, 2H) CHs in 5 and 6 of bicycloheptene ring 7.40-7.55
(m, 1H) CH in 6 of benzopyran ring 8.30-8.40 (m, 1H) CH in 7(5) of
benzopyran ring 8.45-8.55 (m, 1H) CH in 5 (7) of benzopyran ring
10.10-12.10 (bb, 1H) COOH
2-Cycloheptyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid
Intermediate CLIX
A mixture, of 7.3 g of methyl 2-hydroxy-3-propionylbenzoate, 4.7 g
of 4-dimethylaminopyridine and 50 ml of dichloromethane was stirred
at room temperature. Cycloheptanecarbonyl chloride, 56 g, in 10 ml
of dichloromethane, (prepared as described in P. W. Collins et al.,
J. Med. Chem. 32, 1001-1006 (1989)) was added to the solution using
dropwise addition. The mixture was stirred at room temperature for
5 hours and allowed to stand overnight. The reaction mixture was
washed, in succession, with 3% hydrochloric acid, saturated aqueous
sodium bicarbonate solution and water. This was followed by drying
over anhydrous sodium sulfate and evaporation to dryness to provide
9.8 g of crude methyl
2-cycloheptanecarbonyloxy-3-propionylbenzoate. This product was
utilized without further purification.
A mixture of 7.66 g of the ester prepared above and 1 ml of
1,8-diazabicyclo[5,4,0]-undec-7-ene in 20 ml of anhydrous pyridine
was stirred for 1 hour at 100.degree. C. After cooling to room
temperature, the solvent was evaporated (in vacuo) and 60 ml of
water was added to the residue. The mixture was extracted with
ethyl acetate. The organic layer was washed, in succession, with 3%
hydrochloric acid, saturated aqueous sodium bicarbonate solution
and water. This was followed by drying over anhydrous sodium
sulfate. Evaporation to dryness (in vacuo) provided the crude
methyl ester of the title compound. It was purified by flash
chromatography on silica gel eluting with petroleum ether/ethyl
acetate (9:1) and used for the following hydrolysis.
The purified intermediate prepared above (2 g) was hydrolyzed
according to the procedure of Intermediate LXVII. The reaction was
carried out at room temperature for 4.5 hours using a mixture of
1,4-dioxane-methanol (3:7) instead of ethanol. The title compound
was purified by crystallization from acetonitrile to provide 1.6 g
of solid, m.p. 212.degree.-215.degree. C.
.sup.1 H-NMR Spectrum at 200 MHz (DMSO-d6, (.delta.)) 1.48-1.75 (m,
6H) CH.sub.2 s of cycloheptane ring 1.75-1.95 (m, 6H) CH.sub.2 s of
cycloheptane ring 2.00 (s, 3H) CH.sub.3 in 3, benzopyran ring
3.05-3.20 (m, 1H) CH in 1, cycloheptane ring 7.49 (dd, 1H) CH in 6,
benzopyran ring 8.15 (dd, 1H) CH in 7(5), benzopyran ring 8.20 (dd,
1H) CH in 5 (7), benzopyran ring 13.10-13.60 (bs, 1H) COOH
Methyl 4-chloro-2-phenylquinoline-8-carboxylate Intermediate
CLX
A mixture of 7 g of 2-phenyl-4(1H)-quinolone-8-carboxylic acid
(prepared as described by W. A. Denny et al., J. Med. Chem., 32,
396 (1989)) and 60 ml of phosphorus oxychloride was stirred at
reflux temperature for .sub.40 minutes. After cooling to room
temperature, the mixture was poured into 500 g of ice water,
neutralized with 12N sodium hydroxide solution and extracted with
chloroform. The organic layer was washed with water, dried over
anhydrous sodium sulfate and evaporated to dryness (in vacuo) to
provide the crude product. The product was purified by flash
chromatography on silica gel eluting with petroleum ether/ethyl
acetate (9:1). Crystallization from ethanol provided 3.6 g of the
title compound, m.p. 98.degree.-101.degree. C.
Methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-8-carboxylate
Intermediate CLXI
Chloro-ester Intermediate CLX, (3.63 g) was reduced, in a Parr
apparatus in a hydrogen atmosphere at 45 psi, in a mixture of 1.21
g of anhydrous sodium acetate, 30 ml of methanol, 0.73 g of Raney
nickel and 91 ml of ethyl acetate. After the theoretical hydrogen
absorption, the insoluble material was separated by suction
filtration, the filtrate was concentrated to a small volume (in
vacuo), diluted with water and extracted with ethyl acetate. The
organic layer was separated, washed with saturated aqueous sodium
bicarbonate solution and water. The crude product was obtained by
evaporation of the solvent. Crystallization from ethanol provided
2.1 g of the title compound, characterized by NMR spectrum as
follows.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3, (.delta.)) 1.85-2.25
(m, 2H) CH.sub.2 in 3, tetrahydroquinoline ring 2.65-2.95 (m, 2H)
CH.sub.2 in 4, tetrahydroquinoline ring 3.82 (s, 3H) CH.sub.3 4.62
(m, 1H) CH in 2, tetrahydroquinoline ring 6.50 (dd, 1H) CH in 6,
tetrahydroquinoline ring 7.10 (dd, 1H) CH in 5, tetrahydroquinoline
ring 7.20-7.40 (m, 5H) CHs of phenyl ring 7.75 (dd, 1H) CH in 7,
tetrahydroquinoline ring 8.08 (s, 1H) NH
Methyl 1-methyl-2-phenyl-1,2,3,4-tetrahydroquinoline-8-carboxylate
Intermediate CLXII
A mixture of 0.21 g of Intermediate CLXI, 0.23 g of
paraformaldehyde, 0.15 g of sodium borohydride and 7.8 ml of
tetrahydrofuran was stirred and maintained at room temperature.
Trifluoroacetic acid 3.8 ml was added, using dropwise addition to
the solution. The mixture was stirred at room temperature for 26
hours, then poured into 100 ml of cooled water and alkalinized by
addition of 7 ml of 12N sodium hydroxide solution. After saturation
with sodium chloride, the mixture was extracted with diethyl ether,
the organic layer was separated, dried over anhydrous sodium
sulfate and evaporated to dryness to provide 0.25 g of the title
compound as an oily residue, characterized by NMR spectrum as
follows.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl3, (.delta.)) 1.80-2.00 (m,
1H) CH in 3, tetrahydroquinoline ring 2.20-2.40 (m, 1H) CH in 3,
tetrahydroquinoline ring 2.60-2.95 (m, 2H) CH.sub.2 in 4,
tetrahydroquinoline ring 2.71 (s, 3H) NCH.sub.3 3.86 (s, 3H)
OCH.sub.3 4.25-4.40 (m, 1H) CH in 2, tetrahydroquinoline ring 6.65
(dd, 1H) CH in 6, tetrahydroquinoline ring 7.05 (dd, 1H) CH in 5,
tetrahydroquinoline ring 7.20-7.45 (m, 5H) CHs of phenyl ring 7.50
(dd, 1H) CH in 7, tetrahydroquinoline ring
1-Methyl-2-phenyl-1,2,3,4-tetrahydroquinoline-8-carboxylic acid
Intermediate CLXIII
This compound was prepared according to the procedure used for
Intermediate LXVII, starting from Intermediate CLXII instead of
Intermediate LXVI and using potassium hydroxide instead of sodium
hydroxide. The reaction was continued for 12 hours at 90.degree. C.
using a mixture of ethanol/1,4-dioxane (5:3) instead of ethanol.
The title compound was characterized by NMR spectrum as
follows.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3, (.delta.)) 2.30-2.45
(m, 2H) CH.sub.2 in 3, tetrahydroquinoline ring 2.60 (s, 3H)
NCH.sub.3 2.95-3.05 (m, 2H) CH.sub.2 in 4, tetrahydroquinoline ring
4.30-4.40 (m, 1H) CH in 2, tetrahydroquinoline ring 7.25 (dd, 1H)
CH in 6, tetrahydroquinoline ring 7.30-7.45 (m, 6H) CH in 5,
tetrahydroquinoline ring and CHs of phenyl ring 8.05 (dd, 1H) CH in
7, tetrahydroquinoline ring 14.90-15.50 (bs, 1H) COOH
(Trans)-methyl
2-(4-methoxycyclohexyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CLXIV and
(Cis)-methyl
2-(4-methoxycyclohexyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylate
Intermediate CLXV
The title compounds were prepared following the procedure described
for Intermediate CXLVIII, starting from 4.9 g of
4-methoxycyclohexancarboxylic acid (cis-trans mixture).
Purification and resolution of the crude products by flash
chromatography (eluent petroleum ether/ethyl acetate 8:2) provided
1.54 g of trans Intermediate CLXIV and 1.10 g of cis Intermediate
CLXV as amorphous solids characterized by NMR as follows.
.sup.1 H-NMR Spectra at 200 MHz (CDCl.sub.3 (.delta.)):
Intermediate CLXIV (trans) 8.40 (1H, dd) CH in 7(5), benzopyran
8.22 (1H, dd) CH in 5(7), benzopyran 7.39 (1H, dd) benzopyran, CH
in 6 4.00 (3H, s) COOCH.sub.3 3.41 (3H, s) OCH.sub.3 eq. 3.20-3.40
(1H, m) CHOCH.sub.3 ax. 2.80-3.00 (1H, m) cyclohexyl, CH in 1, ax.
2.18-2.32 (2H, m) cyclohexyl, CHs 2.10 (3H, s) CH.sub.3 C 1.88-2.03
(4H, m) cyclohexyl, CHs 1.22-1.48 (2H, m) cyclohexyl, CHs
Intermediate CLXV (cis,) 8.40 (1H, dd) CH in 7(5), benzopyran 8.22
(1H, dd) CH in 5(7), benzopyran 7.39 (1H, dd) benzopyran, CH in 6
4.05 (3H, s) COOCH3 3.52-3.62 (1H, m) CHOCH3, eq. 3.37 (3H, s)
OCH3, ax. 2.85-3.05 (1H, m) cyclohexyl, CH in 1, ax. 2.05-2.32 (7H,
m) CH3C and cyclohexyl CHs 1.43-1.78 (4H, m) cyclohexyl CHs
(Trans)-2-(4-methoxycyclohexyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic
acid Intermediate CLXVI
The title compound was prepared as described for Intermediate
CXXXVI starting from Intermediate CLXIV instead of Intermediate
CXXXV. Filtration of the solid after acidification of the alkaline
solution, provided the title compound, m.p. 202.degree.-209.degree.
C.
(Cis)-2-(4-methoxycyclohexyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic
acid Intermediate CLXVII
The title compound was prepared as described for Intermediate
CXXXVI starting from Intermediate CLXV instead of Intermediate
CXXXV. After acidification of the alkaline solution, filtration of
the solid provided the title compound m.p. 195.degree.-197.degree.
C.
2-Hydroxy-N,3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl-3-propionylbenzamid
e dihydrochloride Intermediate CLXVIII
A solution of 7.48 g of
1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine in 30 ml of
dichloromethane was added dropwise within 45 minutes at 4.degree.
C. into a stirred mixture of 6.37 g of 2-hydroxy-3-propionylbenzoyl
chloride (prepared as described in DE 2,631,248) and 4.2 ml of
triethylamine in 80 ml of dichloromethane. The reaction mixture was
stirred for 2 hours at 4.degree. C. and for 8 hours at room
temperature, then it was extracted with 5% aqueous sodium hydrogen
carbonate solution followed by water and the organic layer was
dried over anhydrous sodium sulfate. The residue obtained by
evaporation in vacuo of the solvent was purified by flash
chromatography on silica gel eluting with dichloromethane-methanol
98:2 to 95:5. The fractions containing the pure base were confined,
the solvent were evaporated (in vacuo), the residue was dissolved
in ethanol and an excess of ethanolic hydrogen chloride was added.
This was followed by addition of diethyl ether until the salt
crystallized. Crystallization from methanol provided 7.6 g of the
title compound, m.p. 215.degree.-217.degree. C. (decompose).
8-Trifluoroacetamidomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
This compound can be prepared according to the procedure described
for Intermediate XXIII, but using Intermediate XXIV instead of
8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.
It can be used as starting material instead of Intermediate XXIII,
in the same reaction as that described in Example 32 to yield
8-{2[4-(2-methoxyphenyl)-1-piperazinyl]ethylamino}-methyl-3-methyl-4-oxo-2
-phenyl-4H-1-benzopyran.
8-(2-Chloroethylureido)methyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
This intermediate can be prepared operating as described for
Intermediate XLIV by using Intermediate XXIV instead of
8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.
It can be reacted with a compound of formula H-B, according to Path
(a) to give the desired final compounds.
8-Ethenylsulfonylaminomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
This compound can be prepared by reacting Intermediate XXIV with
2-chloroethylsulfonylchloride in an halogenated solvent (e.g.,
dichloromethane) in presence of triethylamine at
0.degree.-40.degree. C., according to A. A. Goldberg, Jr., J. Chem.
Soc., 464 (1945).
It can be reacted with the appropriate compounds H-B, according to
Path (m) to yield the desired final compounds.
8-Chlorosulfonylmethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
This intermediate can be prepared by reacting
amidinothiomethyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (whose
synthesis is described in Intermediate XXI) with chlorine gas in
water at -10.degree./10.degree. C. according to T. B. Johnson et
al., J. Am. Chem. Soc., 61, 2548 (1939). By reaction of this
intermediate with the appropriate compounds
A-NH-Z-B(A=H,OR,CH.sub.3) according to Path (n) the final desired
compounds can be obtained.
DETAILED SYNTHESIS OF EXAMPLES
Example 1
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-1-oxoethyl}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran hydrochloride
A solution of 11.5 g of 1-(2-methoxyphenyl)-piperazine in 30 ml of
methanol was added dropwise at 20.degree.-25.degree. C. to a
stirred mixture consisting of 21.4 g of Intermediate VI and 4.1 g
of potassium carbonate in 120 ml of methanol. After 4 hours
stirring at the same temperature, the reaction mixture was stripped
in vacuo. The residue was extracted with chloroform and the organic
solution was washed with water, dried on anhydrous sodium
sulfate/calcium chloride, filtered and stripped in vacuo. The
obtained crude product was dissolved in acetone and a slight excess
of ethanolic hydrogen chloride was added. After collection by
suction filtration and recrystallization from 95% ethanol, 16.3 g
of the title compound was obtained (m.p. (189)
195.degree.-199.degree. C.).
Example 2
8-{2-[4-(2-Methylphenyl)-1-piperazinyl]-1-oxoethyl}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran hydrochloride
This compound was prepared according to Example 1, but using
1-(2-methylphenyl)-piperazine instead of
1-(2-methoxyphenyl)-piperazine and carrying out the reaction in
dimethylformamide for 1 hour instead of in methanol for 4 hours,
m.p. (194) 203.degree.-206.degree. C. (2-propanol).
Example 3
8-{2-[4-(2-Ethoxyphenyl)-1-piperazinyl]-1-oxoethyl}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran hydrochloride
This compound was prepared according to Example 1, but using
1-(2-ethoxyphenyl)-piperazine instead of
1-(2-methoxyphenyl)-piperazine and carrying out the reaction in
dimethylformamide for 2 hours instead of in methanol for 4 hours.
m.p. 208.degree.-210.degree. C. (2-propanol).
Example 4
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-1-oxopropyl}-3-methyl-4-oxo-2-phen
yl-4H-1-benzopyran hydrochloride
A solution of 10 ml of 37% formaldehyde in 15 ml of methanol was
dropped, over a period of 3 minutes at 0.degree. C., into a
solution of 5.75 g of 1-(2-methoxyphenyl)piperazine in 10 ml of
methanol. After 12 hours at 0.degree. C., the mixture was stripped
in vacuo and redissolved in 15 ml of methanol. 20 ml of 3.6N
hydrogen chloride in diethyl ether was added at 0.degree. C. After
stripping in vacuo, the residue was suspended in 15 ml of
1,4-dioxane. A solution of 8.3 g of Intermediate V in 100 ml of
1,4-dioxane was added under stirring at 20.degree.-25.degree. C.
After stirring for 8 hours at reflux the reaction mixture was
cooled to 30.degree.-40.degree. C. 50 ml of methanol was added and
the mixture was refluxed for a further 2 hours. After cooling to
20.degree.-25.degree. C., the resultant solution was diluted with
300 ml of diethyl ether. Stirring was continued for a further 3
hours at the same temperature. The title compound was collected by
suction filtration and recrystallization from ethanol. Yield 4 g,
m.p. 209.degree.-210.degree. C.
Example 5
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propoxycarbonyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran dihydrochloride
A mixture of 4.24 g of
8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 6.3 g of
anhydrous potassium carbonate in 60 ml of dimethylformamide was
stirred at 80.degree. C. for 30 minutes. 5.23 g of
1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine was then added
and stirring was continued at 80.degree. C. for 3.5 hours. The
reaction mixture was cooled to ambient temperature, poured on to
iced water and extracted with ethyl acetate. The organic extracts
were washed with aqueous sodium chloride solution, dried on
anhydrous sodium sulfate, and evaporated to dryness in vacuo. The
residue was taken up in ethanol and excess ethanolic hydrogen
chloride was added to the solution. Yield: 8.16 g of the title
compound, m.p. 198.degree.-203.degree. C.
Example 6
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethoxycarbonyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran dihydrochloride
Operating as described in Example 5, but using
1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine instead of
1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine, the title
compound was obtained, m.p. 200.degree.-203.degree. C. from
ethanol.
Example 7
8-{3-[4-(2-Chlorophenyl)-1-piperazinyl]-propoxycarbonyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran dihydrochloride
A mixture of 2.8 g of 1-(2-chlorophenyl)-piperazine hydrochloride
and 4.2 g of anhydrous potassium carbonate in 25 ml of
dimethylformamide was stirred at ambient temperature for 15
minutes. 4.81 g of Intermediate I was added, and stirring was
continued for 2 days. The reaction mixture was then poured into 200
ml of cold water, and extracted with diethyl ether and ethyl
acetate. The organic extracts were washed in turn with aqueous
sodium chloride solution, 0.1N aqueous acetic acid solution,
aqueous sodium chloride solution, aqueous 4% sodium carbonate
solution and water, and were then dried on anhydrous sodium
sulfate. After evaporation to dryness in vacuo, the residue was
dissolved in 160 ml of acetonitrile and excess hydrogen chloride in
diethyl ether was added. The insoluble title compound. was
recrystallized from acetonitrile. Yield 3.6 g, m.p.
138.degree.-143.degree. C.
Example 8
8-[3-(4-Phenyl-1-piperazinyl)-propoxycarbonyl]-3-methyl-4-oxo-2-phenyl-4H-1
-benzopyran dihydrochloride
The title compound was prepared by the method described in Example
7, but using 1-phenyl-piperazine in place of
1-(2-chlorophenyl)-piperazine hydrochloride. Recrystallization was
from methanol; the melting point was 229.degree.-231.degree. C.
Example 9
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propoxycarbonyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran dihydrochloride
Operating as described in Example 7, but using
1-(2-methoxyphenyl)-piperazine hydrochloride instead of
1-(2-chlorophenyl)-piperazine hydrochloride, the title compound was
obtained. This represents an alternative route to the product of
Example 5.
Example 10
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-2-methyl-2-propoxycarbonyl}-3-meth
yl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride
5.29 g of Intermediate XXVIII in 25 ml of 1,2-dichloroethane was
added dropwise at 60.degree. C. to a solution of 6 g of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 22
ml of 1,2-dichloroethane. The reaction mixture was refluxed for 16
hours, and then cooled to ambient temperature and poured into cold
0.5N aqueous sodium hydroxide solution. Water and dichloromethane
were added. The organic phase was separated off, washed with
aqueous sodium chloride solution and dried on anhydrous sodium
sulfate. The solvents were evaporated off and the oily residue was
purified by flash chromatography on silica gel, eluting with
petroleum ether:ethyl acetate (85:15). The collected fractions were
evaporated to dryness in vacuo and the residue was dissolved in
ethanol. Excess ethanolic hydrogen chloride was added to give 6.71
g of the title compound, m.p. 203.degree.-204.degree. C.
Example 11
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran dihydrochloride hemihydrate
A mixture of 6.28 g of 1-(2-methoxyphenyl)-piperazine and 5.34 g of
Intermediate XXXVII was heated at 180.degree. C. for 5 hours. After
cooling, the dark mass was purified by flash chromatography on
silica gel, eluting with dichloromethane: methanol (100:3). The
fractions containing the title compound were pooled. The solvents
were removed in vacuo and the residue was dissolved in boiling
ethanol. The solution was filtered, acidified with ethanolic
hydrogen chloride, and stood overnight at 20.degree.-25.degree. C.
The crude product was collected by filtration and crystallized from
ethanol to give 5 g of the title compound, m.p. (177)
182.degree.-186.degree. C.
Example 12
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran dihydrochloride hemihydrate
A solution of 4.48 g of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride in 40
ml of chloroform was added dropwise over a period of 10 minutes at
ambient temperature to a solution of 3.74 g of
3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine (prepared as in
British Patent No. 2,161,807) and 1.97 g of triethylamine in 50 ml
of chloroform. After stirring for 2 hours, the solution was washed
first with 0.5N aqueous hydrochloric acid solution, secondly with a
saturated aqueous sodium bicarbonate solution and finally with
water. The chloroform solution was dried on anhydrous sodium
sulfate and the solvent was evaporated off in vacuo. The residue
was worked up as described in Example 11 to give 6.67 g of the
title compound, m.p. (177) 182.degree.-186.degree. C. This
represents an alternative route to the product of Example 11.
The following salts were also prepared:
monohydrochloride hydrate, m.p. 151.degree.-154.degree. C.,
monomethanesulfonate, m.p. 162.degree.-164.degree. C., and
monomethanesulfonate, monohydrate m.p. 136.degree.-141.degree.
C.,
(.+-.)-hemimalate hydrate, m.p. 110.degree.-112.degree. C.
The title compound was isolated as the anhydrous base, m.p.
133.degree.-136.degree. C. (2-propanol or ethyl acetate).
Recrystallization of the anhydrous base from an acetonitrile-water
mixture (2:1) provided the base contained 0.25 molar equivalents of
water, m.p. 104.degree.-106.degree. C.
This example has described the condensation of the amine,
3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamine, with the
carbonyl chloride,
3-methyl-4-oxo-2-phenyl-4H-1benzopyran-8-carbonyl chloride. It
should be noted that the amine can be condensed with the
corresponding free acid or the corresponding ethyl ester by heating
equimolar amounts thereof with or without a solvent. If a solvent
is used, a high boiling point hydrophilic or hydrophobic solvent is
appropriate. The amine can also be condensed at room temperature
with an equimolar amount of the corresponding free acid in the
presence of N,N'-dicyclohexylcarbodiimide and
4-dimethylaminopyridine in a solvent such as dichloromethane,
chloroform, tetrahydrofuran, or dimethylformamide.
Example 13
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran monohydrochloride hemihydrate
The title compound was prepared by the method described in Example
16, but using Intermediate XIV instead of Intermediate XV and
heating at 55.degree.-60.degree. C. for 32 hours. Also, work up was
varied as follows. After collecting the base by filtration,
purification was by flash chromatography on silica gel, eluting
with a chloroform:methanol gradient (100:0.5 and then 100:1). The
fractions containing the title compound were pooled and the
solvents were removed in vacuo. The residue was crystallized from
ethanol. After filtration, the solids were taken up in boiling
water and sufficient dilute hydrochloric acid was added to effect
solution. The crystalline salt separated on cooling and was
collected by suction filtration. m.p. 119.degree.-123.degree.
C.
Example 14
8-{3-[2-(2-Methoxyphenoxy)-ethylamino]-propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran hydrochloride
Operating as described in Example 11, but using
2-(2-methoxyphenoxy)-ethylamine (prepared according to Augstein, J.
et al., J. Med. Chem. 8: 356, 1965) instead of
1-(2-methoxyphenyl)piperazine, heating for 2 hours instead of 5
hours, and using dichloromethane:methanol (100:5) as eluant, the
title compound was obtained, m.p. 200.degree.-202.degree. C.
(ethanol).
Example 15
8-[3-(4-Phenyl-1-piperazinyl)-propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1
-benzopyran monohydrochloride hemihydrate
Operating as described in Example 11, but using 1-phenylpiperazine
instead of 1-(2-methoxyphenyl)-piperazine and heating for 2 hours
instead of 5 hours, and using dichloromethane:methanol 100:4 as
eluant, the title compound was obtained. m.p. (251)
255.degree.-258.degree. C. with decomposition (87% ethanol).
Example 16
8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran monohydrochloride
A mixture of 3.56 g of Intermediate XV, 2.35 g of
1-(2-methoxyphenyl)-piperazine, 2.76 g of anhydrous potassium
carbonate and 1.66 g of potassium iodide in 25 ml of
dimethylformamide was stirred at 100.degree. C. for 6 hours. After
cooling, the solvent was removed in vacuo and the residue was taken
up in 50 ml of water, stirred for 1 hour at room temperature,
collected by filtration, washed with water and crystallized from
95% ethanol in the presence of a small amount of activated charcoal
(for decoloring). The base was dissolved in 105 ml of boiling
0.086N aqueous hydrochloric acid solution. After cooling, the
crystallized salt was collected by filtration, giving 4.3 g of the
title compound (m.p. 201.degree.-203.degree. C.).
Example 17
8-{1-Hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran hydrochloride
1.36 g of sodium borohydride was added portionwise at 0.degree. to
+5.degree. C. to a solution of 15.5 g of the compound prepared in
Example 1 in 1500 ml of methanol. After stirring for 90 minutes at
0.degree. to +5.degree. C., 3N aqueous hydrochloric acid solution
was added in order slightly to acidify the reaction mixture, which
was then stripped in vacuo. The residue was shaken with 2N aqueous
sodium hydroxide solution and extracted with chloroform. The
organic layer was dried on anhydrous sodium sulfate/calcium
chloride, filtered, acidified with ethanolic hydrogen chloride and
stripped in vacuo. After washing with diethyl ether, the crude
product was crystallized from ethanol to give 9.5 g of title
compound, m.p. 248.degree.-249.degree. C.
Example 18
8-{1-Hydroxy-2-[4-(2-methylphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran hydrochloride
This compound was prepared according to Example 17, but starting
from the compound prepared in Example 2, rather than that prepared
in Example 1. m.p. 257.degree.-258.degree. C. (ethanol).
Example 19
8-{1-Hydroxy-2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran hydrochloride
This compound was prepared according to Example 17, but starting
from the compound prepared in Example 3 rather than that prepared
in Example 1. m.p. 241.degree.-242.degree. C. (methanol).
Example 20
8-{1-Hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-3-methyl-4-oxo-2
-phenyl-4H-1-benzopyran hydrochloride
This compound was prepared according to Example 17, but starting
from the compound prepared in Example 4 rather than that prepared
in Example 1. The crude base was purified by flash chromatography
(silica gel, eluant - ethyl acetate: chloroform (4:1). The
fractions containing the pure base were pooled, acidified with
ethanolic hydrogen chloride and stripped in vacuo. The residue was
crystallized from ethanol. m.p. (126) 156.degree.-160.degree.
C.
Example 21
8-{1-Hydroxy-4-[4-(2-methoxyphenyl)-1-piperazinyl]-butyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran hydrochloride monohydrate
A solution of 3.04 g of Intermediate XXXVIII and 2.45 g of
1-(2-methoxyphenyl)-piperazine in 21 ml of anhydrous
dimethylformamide was stirred for 5 hours at ambient temperature. A
further 1.22 g of 1-(2-methoxyphenyl)-piperazine was added, and the
mixture was stirred for 4 hours, poured into 300 ml of water, and
extracted with ethyl acetate. The combined organic extracts were
washed with aqueous sodium bicarbonate solution and then with
aqueous sodium chloride solution, and evaporated to dryness in
vacuo. The residue was purified by flash chromatography on silica
gel, eluting with ethyl acetate:methanol (95:5). The collected
fractions were stripped on a rotary evaporator, and the residue was
dissolved in 0.81M ethanolic hydrogen chloride and stripped again
in vacuo. The solid residue was crystallized from water:ethanol
(9:1) to give 2.43 g of the title compound, m.p.
144.degree.-146.degree. C.
Example 22
8-{1-Ethoxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran hydrochloride
6 ml of anhydrous dimethylsulfoxide was added to 6.55 g of sodium
hydride (50% in mineral oil, repeatedly washed with hexane) under
nitrogen. A solution of 3 g of the compound prepared in Example 17
in 50 ml of anhydrous dimethylsulfoxide was added to the mixture at
20.degree.-25.degree. C. After stirring for 1 hour at 20.degree.
C., 0.66 g of ethyl bromide was added. The reaction mixture was
stirred for an additional 20 minutes at the same temperature and
then poured into iced water. The crude product obtained after
suction filtration was purified by flash chromatography (silica
gel, eluant - chloroform:ethyl acetate (8:2). The fractions
containing the pure title compound were pooled, acidified with
ethanolic hydrogen chloride, and stripped in vacuo. The residue was
crystallized from chloroform:diethyl ether and dried in vacuo at
140.degree. C. to give 1.6 g of the title compound, m.p. (155)
209.degree. C.
Example 23
8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylaminomethyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride
A mixture of 5.2 g of Intermediate XXVII, 3.1 g of
1-(2-methoxyphenyl)-piperazine and 2.2 g of anhydrous potassium
carbonate in 50 ml of dimethylformamide was stirred at 70.degree.
C. for 7 hours. After cooling to 20.degree.-25.degree. C., the
reaction mixture was poured into 500 ml of water, and extracted
with dichloromethane. The organic phase was washed with water and
dried on anhydrous sodium sulfate. The solvent was removed in
vacuo. The residue was purified by flash chromatography on silica
gel, eluting with ethyl acetate:petroleum ether (98:2). The title
compound was obtained by salification with ethanolic hydrogen
chloride. m.p. 217.degree.-219.degree. C.
Example 24
8-{N-acetyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylaminomethyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride
A mixture of 5 g of Intermediate XXXIII and 5.3 g of
1-(2-methoxyphenyl)-piperazine in 75 ml of dimethylformamide was
stirred at 95.degree. C. for 2 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 200
ml of water, made alkaline with potassium carbonate and extracted
with ethyl acetate. The organic phase was washed with water and
dried on anhydrous sodium sulfate. The solvent was removed in
vacuo. The residue was purified by flash chromatography on silica
gel, eluting with dichloromethane:methanol (100:0.2). Salification
of the pure base with ethanolic hydrogen chloride and
recrystallization from methanol gave 4.4 g of the title compound,
melting at (200) 227.degree.-228.degree. C. and containing one
equivalent of methanol.
Example 25
8-[4-(2-Methoxyphenyl)-1-piperazinylacetamidomethyl]-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran hydrochloride
A mixture of 3.42 g of Intermediate XXXII, 2.74 g of
1-(2-methoxyphenyl)-piperazine and 0.71 g of anhydrous potassium
carbonate in 34 ml of anhydrous dimethylformamide was stirred at
0.degree. C. for 2 hours. The reaction mixture was poured into
water and filtered under suction. The resultant solid was purified
by flash chromatography on silica gel, eluting with ethyl
acetate:petroleum ether (6:4). The collected fractions were
evaporated to dryness in vacuo, and the residue was crystallized
from ethyl methyl ketone. The base obtained was treated in
ethanolic solution with a molar equivalent of aqueous 2.25N
hydrochloric acid to give the title compound, m.p.
168.degree.-170.degree. C.
Example 26
8-{N-methyl-[4-(2-methoxyphenyl)-1-piperazinyl]-acetamido-methyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran hydrochloride hydrate
A mixture of 5 g of Intermediate XXXI, 2.9 g of
1-(2-methoxyphenyl)-piperazine and 2 g of anhydrous potassium
carbonate in 50 ml of dimethylformamide was stirred at
20.degree.-25.degree. C. for 3 hours. The reaction mixture was then
poured into 500 ml of water and extracted with dichloromethane. The
organic phase was washed with water and dried on anhydrous sodium
sulfate. The solvent was removed in vacuo. The residue was purified
by flash chromatography on silica gel, eluting with ethyl acetate:
petroleum ether (6:4), and crystallized from acetone to give 3.6 g
of the base of the title compound, melting at
144.degree.-145.degree. C. The base was dissolved in ethanol, and
8N hydrochloric acid and water were added, yielding the title
compound, m.p. 218.degree.-220.degree. C. after drying at
100.degree. C. in vacuo.
Example 27
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethoxymethyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran dihydrochloride
A mixture of 4 g of Intermediate XVIII, 2.4 g of
1-(2-methoxyphenyl)piperazine, 1.96 g of potassium iodide and 1.65
g of anhydrous potassium carbonate in 40 ml of anhydrous
dimethylformamide was stirred at 90.degree. C. for 7 hours. After
cooling to ambient temperature, the mixture was poured into water
and extracted with dichloromethane. The combined extracts were
washed with aqueous sodium chloride solution, dried on anhydrous
sodium sulfate and evaporated to dryness in vacuo. The residue was
crystallized from ethyl acetate and the collected crystals were
dissolved in ethanol and treated with excess ethanolic hydrogen
chloride to give 5.21 g of the title compound, m.p.
199.degree.-201.degree. C.
Example 28
8-{2-[2-(2-Ethoxyphenoxy)-ethylamino]-ethoxymethyl}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran hydrochloride
Operating as described in Example 27, but using
2-(2-ethoxyphenoxy)-ethylamine in place of
1-(2-methoxyphenyl)piperazine and including a purification step of
flash chromatography on silica gel eluted with ethyl
acetate:methanol (97:3), 4.25 g of the title compound was obtained.
m.p. 191.degree.-193.degree. C.
Example 29
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethylthiomethyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran hydrochloride
2.5 g of potassium carbonate, 2.13 g of potassium iodide and 3.15 g
of 1-(2-methoxyphenyl)-piperazine were added to a solution of 5 g
of Intermediate XXI in 50 ml of dimethylformamide, and the mixture
was stirred at 90.degree. C. for 4.5 hours. After cooling to
ambient temperature, the reaction mixture was poured into 450 ml of
water and extracted with ethyl acetate. The organic extracts were
washed with water, dried on anhydrous sodium sulfate and evaporated
to dryness in vacuo. A solution of the residue in acetone was
treated with a molar equivalent of 3.8N hydrogen chloride in
diethyl ether, filtered and recrystallized from ethanol to yield
6.15 g of the title compound, m.p. (218) 223.degree.-224.degree.
C.
Example 30
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethylsulfinylmethyl}-3-methyl-4-ox
o-2-phenyl-4H-1-benzopyran dihydrochloride hemihydrate
The title compound was prepared by the method described in Example
29, using Intermediate XXVI instead of Intermediate XXI and
stirring for 2.5 hours rather than for 4.5 hours. After the usual
work up, the residue was purified by flash chromatography on silica
gel, eluting with ethyl acetate:methanol (97:3). The collected
fractions were acidified with excess ethanolic hydrogen chloride,
evaporated to dryness in vacuo. The residue was crystallized from
ethanol, giving 5.2 g of the title compound, m.p.
170.degree.-172.degree. C. This compound contains 1 equivalent of
ethanol.
Example 31
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethylsulfonylmethyl}-3-methyl-4-ox
o-2-phenyl-4H-1-benzopyran hydrochloride
A mixture of 4.5 g of Intermediate XXV, 2.36 g of
1-(2-methoxyphenyl)-piperazine and 0.84 g of potassium carbonate in
45 ml of anhydrous dimethylformamide was stirred at ambient
temperature for 2.5 hours. The reaction mixture was poured into 300
ml of water and filtered under suction, washing with water. The
solid base was crystallized from ethanol and had a melting point of
143.degree.-146.degree. C. The crystals were dissolved in
1,2-dichloroethane and acidified with ethanolic hydrogen chloride.
4.4 g of the title compound, m.p. 229.degree.-233.degree. C., was
obtained by recrystallization from methanol:water (1:3.5).
Example 32
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethylamino}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran dihydrochloride
A solution of 3.7 g of Intermediate XXIII in 10 ml of
dimethylformamide was added dropwise at 0.degree. C. to a
suspension of 0.9 g of sodium hydride (50% in mineral oil) in 9 ml
of dimethylformamide. The cooling bath was removed, and after 30
minutes at 20.degree.-25.degree. C. a solution of 4.1 g of
1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 10 ml of
dimethylformamide was added. The mixture was stirred at 90.degree.
C. for 5 hours and then cooled to 20.degree.-25.degree. C. A
further addition of 0.25 g of sodium hydride (50% in mineral oil)
followed by 1.36 g of
1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 5 ml of
dimethylformamide was made. The mixture was stirred at 90.degree.
C. for 8 hours and again cooled to 20.degree.-25.degree. C. 200 ml
of water was cautiously added, and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and dried on
anhydrous sodium sulfate. The solvent was evaporated off in vacuo
and the residue was purified by flash chromatography on silica gel,
eluting with n-hexane:ethyl acetate (3:2). This gave a mixture of
the base of the title compound and the corresponding
N-trifluoroacetyl compound.
3.8 g of this mixture was dissolved in 35 ml of ethanol and 35 ml
of dimethylsulfoxide. To this solution, 0.55 g of sodium
borohydride was added portionwise at 20.degree.-25.degree. C. The
mixture was stirred for 3 hours at this temperature, and then
poured into 200 ml of water and extracted with ethyl acetate. The
organic extracts were washed with water, dried on anhydrous sodium
sulfate and evaporated to dryness in vacuo. The residue was
dissolved in dichloromethane. 2 equivalents of ethanolic hydrogen
chloride were added to give the title compound, which was
recrystallized from ethanol. Yield 3.8 g, m.p.
231.degree.-234.degree. C.
Example 33
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-oxo-2-phen
yl-4H-1-benzopyran hydrochloride 2.75-hydrate
Using 1-(3-chloropropyl)-4-(2-methoxyphenyl)-piperazine instead of
1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine, but otherwise
operating as described in Example 32, the title compound was
obtained. m.p. 206.degree.-208.degree. C. (10% ethanol).
Example 34
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]-butylamino}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran hydrochloride hemihydrate
A mixture of 4.5 g of Intermediate XXXIX, 3.9 g of
8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 8.3 g of sodium
triacetoxyborohydride and 3.4 ml of acetic acid in 40 ml of
1,2-dichloroethane was stirred for 6 hours at 20.degree.-25.degree.
C. 15 ml of 5% aqueous sodium bicarbonate solution was then added,
and the mixture was stirred for 10 minutes. The mixture was then
made alkaline by addition of 0.5N aqueous sodium hydroxide solution
and extracted with dichloromethane. The organic extracts were
washed with water and dried on anhydrous sodium sulfate. The
solvent was evaporated off in vacuo and the residue was purified by
flash chromatography on silica gel, eluting with ethyl acetate:
petroleum ether 9:1. The base obtained was dissolved in
dichloromethane and 1 equivalent of ethanolic hydrogen chloride was
added. After removing the solvent in vacuo, the residue was
crystallized from 50% ethanol to give 1.6 g of the title compound,
m.p. (140) 151.degree.-153.degree. C.
Example 35
8-{N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran hydrochloride hemihydrate
A mixture of 4 g of the compound prepared in Example 33, in the
form of its base, 4.35 ml of 37% aqueous formaldehyde and 1.15 g of
sodium cyanoborohydride in 25 ml of acetonitrile was stirred at
20.degree.-25.degree. C., maintaining the pH in the range 5-6 by
the addition of acetic acid during the reaction. After 4 hours the
solvent was evaporated off in vacuo. 80 ml of ethyl acetate and 200
ml of ice cooled 1N aqueous sodium hydroxide solution were added to
the residue. The organic phase was washed with water, dried on
anhydrous sodium sulfate and evaporated to dryness in vacuo. The
residue was purified by flash chromatography on silica gel, eluting
with ethyl acetate:petroleum ether (3:1). The pure base which was
obtained was dissolved in diethyl ether. 1 equivalent of ethanolic
hydrogen chloride was added and the solvent was removed in vacuo.
The residue was crystallized from water to give 2 g of the title
compound, m.p. 186.degree.-187.degree. C.
Example 36
8-{N-acetyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran hydrochloride hydrate
A mixture of 4.8 g of the compound prepared in Example 33, in the
form of its base, 2.8 ml of acetic anhydride and 33 ml of pyridine
was stirred at 80.degree. C. for 4 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 200
g of iced water containing 40.8 ml of 10N aqueous hydrochloric acid
solution and extracted with dichloromethane. The organic extracts
were washed with water, dried on anhydrous sodium sulfate and
evaporated to dryness in vacuo. The residue was purified by flash
chromatography on silica gel, eluting with ethyl acetate:methanol
(95:5). The pure base which was obtained was dissolved in
dichloromethane. 1 equivalent of ethanolic hydrogen chloride was
added and the solvent was removed in vacuo. The residue was
crystallized from acetonitrile to give 3 g of the title compound
containing 0.33 equivalents of acetonitrile, m.p.
208.5.degree.-210.5.degree. C.
Example 37
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propionamido}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran hydrochloride
A mixture of 3.97 g of Intermediate X and 3.07 g of
1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was
stirred at 60.degree. C. for 6 hours. The reaction mixture was then
cooled to ambient temperature and poured into water. Following.
extraction with dichloromethane, the organic phase was washed with
water and dried on anhydrous sodium sulfate. The solvent was
removed in vacuo. The crude residue was crystallized from ethanol
to give the base of the title compound, which was then dissolved in
hot ethanol. 1 molar equivalent of 0.81M ethanolic hydrogen
chloride was added to the solution. 4 g of the title compound, m.p.
255.degree.-257.degree. C., was obtained.
Example 38
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethylureido}-3-methyl-4-oxo-2-phen
yl-4H-1-benzopyran methanesulfonate
A mixture of 3.34 g of Intermediate XLIV and 7.22 g of
1-(2-methoxyphenyl)-piperazine was stirred at 100.degree. C. for 5
hours. An additional 1.8 g of 1-(2-methoxyphenyl)-piperazine was
then added and stirring was continued for a further 2 hours at
100.degree. C. After cooling to ambient temperature, the reaction
mixture was poured into water and extracted with ethyl acetate. The
organic phase was washed with aqueous sodium hydroxide solution,
dried on anhydrous sodium sulfate and evaporated to dryness in
vacuo. The crude residue was purified by flash chromatography on
silica gel, eluting with ethyl acetate: methanol (98:2). The
collected fractions were evaporated to dryness in vacuo and
crystallized from water:ethanol (4:6). The crystals were
redissolved in dichloromethane and treated with 1 molar equivalent
of methanesulfonic acid. The crude methanesulfonate obtained by
evaporation in vacuo was crystallized from ethyl acetate:ethanol
(1:1) to yield 2.35 g of the title compound, melting at
191.degree.-193.degree. C.
Example 39
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethoxy}-3-methyl-4-oxo-2-phenyl-4H
-1-benzopyran hydrochloride hydrate
A mixture of 6.61 g of the Intermediate XI, 8.34 g of
1-(2-methoxyphenyl)-piperazine and 1.26 g of sodium iodide in 70 ml
of dimethylformamide was stirred at 80.degree. C. for 17 hours.
After cooling to 20.degree.-25.degree. C., the reaction mixture was
poured into 600 ml of water, made alkaline with 5% aqueous sodium
bicarbonate solution and extracted with dichloromethane. The
organic extracts were washed with aqueous sodium chloride solution,
dried on anhydrous sodium sulfate and evaporated to dryness in
vacuo. The residue was purified by flash chromatography on silica
gel, eluting with a dichloromethane:methanol gradient (99:1, then
98:2). The fractions containing the base of the title compound were
pooled, and the solvent was removed in vacuo. The residue was
dissolved in ethanol and ethanolic hydrogen chloride was added. The
title compound crystallized and was collected by suction
filtration. It was recrystallized from 95% ethanol. Yield 6.5 g,
m.p. 224.degree.-225.degree. C.
Elemental analysis: Found % : C=66.38, H=6.34, N=5.35, Cl=6.76,
H.sub.2 O=3.35 Calculated %: 66.34, 6.14, 5.33, 6.75, 3.43
NMR Spectrum at 60 MHz (CDCl.sub.3 -CD.sub.3 OD) 7.8-7.1 (m,8H)
aromatic protons of the benzopyran ring 7.1-6.6 (m,4H) aromatic
protons of the 2-methoxyphenyl group 4.8-4.4 (m,2H) OCH.sub.2
4.4-4.1 (m,3H) H.sub.2 O and N.sup.+ H 3.9-3.0 (m,10H)
5.times.CH.sub.2 N 3.8 (s, 3H) OCH.sub.3 2.1 (s, 3H) CH.sub.3
Example 40
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propoxy}-3-methyl-4-oxo-2-phenyl-4
H-1-benzopyran dihydrochloride
This compound was prepared by the method described in Example 39,
but using Intermediate IX instead of Intermediate XI. Purification
by flash chromatography was omitted as unnecessary in this case.
m.p. 226.degree.-227.degree. C.
Example 41
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]-butoxy}-3-methyl-4-oxo-2-phenyl-4H
-1-benzopyran dihydrochloride
A mixture of 7.75g of Intermediate XVI, 4.7 g of
1-(2-methoxyphenyl)-piperazine, 3.3 g of potassium iodide and 2.8 g
of anhydrous potassium carbonate in 78 ml of dimethylformamide was
stirred at 75.degree. C. for 2 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 600
ml of water and extracted with dichloromethane. The organic
extracts were washed with water and dried on anhydrous sodium
sulfate, and the solvent was then evaporated off in vacuo. The
residue was purified by column chromatography on silica gel,
eluting with ethyl acetate. The pure title compound thus obtained
as its base was transformed into its dihydrochloride by treatment
with ethanolic hydrogen chloride. After crystallization from
ethanol, 6.5 g of title compound was obtained. m.p.
217.degree.-219.degree. C.
Example 42
8-{5-[4-(2-Methoxyphenyl)-1-piperazinyl]-pentyloxy}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran hydrochloride
This compound was prepared by the method described in Example 41,
but using Intermediate XVII instead of Intermediate XVI. m.p.
173.degree. C. (ethanol). The corresponding base melts at
117.degree.-118.degree. C. (ethanol).
Example 43
8-{3-[4-(2-Methoxyphenyl)-1-oxo-1-piperazinyl]-propoxy}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran 1.75-hydrate
2.93 g of magnesium monoperoxyphthalate in 10 ml of water was added
dropwise at -15.degree. C. to a solution of 4.34 g of the compound
prepared in Example 40 and 0.1 g of benzyl(triethyl) ammonium
chloride in 20 ml of dichloroethane and 20 ml of methanol. The
mixture was stirred for 2 hours at 0.degree. C. and then warmed to
ambient temperature. It was poured into water and made basic by
addition of aqueous sodium hydroxide solution. Extraction with
dichloromethane gave, after the usual work up, a solid which was
purified by flash chromatography, eluting with
dichloromethane:methanol (9:1). The collected fractions containing
the pure compound were evaporated to dryness in vacuo and the
residue was crystallized from acetonitrile to give 0.5 g of the
title compound, m.p. 89.degree.-92.degree. C.
Example 44
8-{2-[2-(2,6-Dimethoxyphenoxy)-ethylamino]-ethoxy}-3-methyl-4-oxo-2-phenyl-
4H-1-benzopyran hydrochloride
A mixture of 4.5 g of Intermediate XII, 3.7 g of triphenyl
phosphine and 2.85 g of 2,6-dimethoxyphenoxy-acetaldehyde (prepared
as per Nelson, W. L. et al., J. Med. Chem. 22: 1125, 1979) in 45 ml
of benzene was stirred at 20.degree.-25.degree. C. for 18 hours and
at reflux for 5 hours. The solvent was evaporated off in vacuo and
the residue was dissolved in 80 ml of anhydrous methanol containing
3.ANG. molecular sieves at 0.degree. C. The mixture was stood for 1
hour at 0.degree. C. and for 1 hour at 20.degree.-25.degree. C.,
and then poured into iced water and extracted with dichloromethane.
The organic extracts were washed with water and dried on anhydrous
sodium sulfate. The solvent was removed in vacuo and the residue
was purified by flash chromatography on silica gel, eluting with
dichloromethane: methanol (49:1). The base obtained was treated
with ethanolic hydrogen chloride. After crystallization from
ethanol, the title compound was obtained. Yield 40%, m.p.
200.degree.-202.degree. C.
Example 45
8-{2-Hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propoxy}-3-methyl-4-oxo-
2-phenyl-4H-1-benzopyran hydrochloride
A solution of 3.7 g of Intermediate XL and 4.64 g of
1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was
stirred at 80.degree. C. for 3 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 400
ml of water and extracted with dichloromethane. The aqueous phase
was made alkaline with 1N aqueous sodium hydroxide solution and
extracted with ethyl acetate. The combined organic extracts were
washed with water and dried on anhydrous sodium sulfate. The
solvents were evaporated off in vacuo. The residue was purified by
flash chromatography on silica gel, eluting with ethyl acetate. The
fractions containing the title compound in the form of its base
were pooled, and stripped in vacuo. The residue was dissolved in
dichloromethane and one equivalent of ethanolic hydrogen chloride
was added. The solvents were removed in vacuo and the residue was
crystallized from ethanol. 5 g of the title compound containing one
molar equivalent of ethanol were obtained. m.p. (122)
126.degree.-128.degree. C. with decomposition.
Example 46
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propylthio}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran
A mixture of 4.4 g of Intermediate XXXIV, 2.5 g of
1-(2-methoxyphenyl)-piperazine, 1 g of potassium iodide and 1.8 g
of anhydrous potassium carbonate in 40 ml of dimethylformamide was
stirred at 100.degree. C. for 3 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 350
ml of water and extracted with dichloromethane. The organic
extracts were washed with water and dried on anhydrous sodium
sulfate, and the solvent was then evaporated off in vacuo. The
residue was purified by column chromatography on silica gel,
eluting with ethyl acetate: petroleum ether 3:2, and by
crystallization from ethanol, yielding 3.9 g of the title compound,
m.p. (70) 96.degree.-99.degree. C.
Example 47
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propylsulfonyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran hydrochloride
A solution of 3.8 g of Intermediate XXXV and 4 g of
1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was
heated at 60.degree. C. for 7 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 500
ml of water and extracted with dichloromethane. The organic
extracts were washed with water and dried on anhydrous sodium
sulfate, and the solvent was then evaporated off in vacuo. The
residue was purified by flash chromatography on silica gel, eluting
with ethyl acetate: petroleum ether (1:1). The base of the title
compound was obtained. It was dissolved in ethanol and one
equivalent of ethanolic hydrogen chloride was added to give 4.5 g
of the title compound, m.p. (215) 226.degree.-228.degree. C.
Example 48
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]-ethylsulfamyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran hydrochloride
A solution of 4.5 g of Intermediate XLII and 3.8 g of
1-(2-methoxyphenyl)-piperazine in 40 ml of dimethylformamide was
heated at 70.degree. C. for 7 hours. After cooling to
20.degree.-25.degree. C., the reaction mixture was poured into 150
ml of water and extracted with dichloromethane. The organic
solution was washed with water and dried on anhydrous sodium
sulfate, and the solvent was then evaporated off in vacuo. The
residue was purified by flash chromatography on silica gel, eluting
with ethyl acetate: petroleum ether (3:7), and the title compound
was obtained by salification with ethanolic hydrogen chloride.
Yield 2.9 g, m.p. 236.degree.-238.degree. C.
Example 49
8-{N-methyl-2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethylsulfamyl}-3-methyl-4
-oxo-2-phenyl-4H-1-benzopyran hydrochloride
The title compound was obtained by the method described in Example
48, but using Intermediate XLI instead of Intermediate XLII. m.p.
194.degree.-198.degree. C. (ethanol).
Example 50
8-{N-aminocarbonyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylamino}-3-met
hyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate hemihydrate
A mixture of 4.06 g of the compound of Example 33 and 1.5 g of
potassium cyanate in 42 ml of glacial acetic acid is stirred at
50.degree. C. for 4 hours. The reaction mixture is poured into iced
water and made alkaline. The precipitate is collected by suction
filtration, dried and purified by flash chromatography using a
silica gel column, eluting with ethyl acetate:methanol (98:2). The
fractions, containing the title product as a base, are evaporated
to dryness in vacuo and an equivalent of methane-sulfonic acid is
added to the residue dissolved in 30 ml of dichloromethane. The
solvent is evaporated off in vacuo and the residue is crystallized
from ethanol to give 3.1 g of the title compound (m.p.
157.degree.-160.degree. C., with decomposition). This compound
contains one molar equivalent of ethanol.
Example 51
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]-1-oxobutyl}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran methanesulfonate
A solution of 1.33 ml of anhydrous dimethylsulfoxide in 9 ml of
dichloromethane is added at -70.degree. C. to a solution of 0.74 ml
of oxalyl chloride in 6 ml of dichloromethane. After stirring at
-70.degree. C. for 15 minutes, a solution of 2.8 g of the compound
of the Example 21 (as a base) in 14 ml of dichloromethane is added.
After 15 minutes at the same temperature, 4.7 ml of anhydrous
triethylamine is added and the temperature is raised to -30.degree.
C. over a period of 30 minutes. Stirring is continued at
-30.degree. C. for another 30 minutes. After letting the
temperature rise to 0.degree. C., the mixture is diluted with 120
ml of water and extracted with dichloromethane. The organic phase
is washed with water, dried on anhydrous sodium sulphate and
evaporated to dryness in vacuo. The residue is purified by flash
chromatography in a silica gel column, eluting with ethyl
acetate:dichloromethane (9:1). The fractions, containing the title
product, are evaporated to dryness in vacuo and one equivalent of
methanesulphonic acid is added to the residue dissolved in 30 ml of
dichloromethane. The solvent is evaporated off in vacuo and the
residue is crystallized from ethanol to give 2.9 g of the title
compound (m.p. 194.degree.-195.degree. C.).
Example 52
8-{3-[2-(1,4-Benzodioxanyl)methylamino]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran methanesulfonate
A mixture of 5.56 g of the Intermediate XLIII, as a base, 4.58 g of
2-(4-toluenesulfonyloxymethyl)-1,4-benzodioxane and 1.9 g of
anhydrous potassium carbonate in 80 ml of anhydrous
dimethylformamide is stirred at 110.degree. C. for 5 hours. The
reaction mixture is cooled to ambient temperature, poured into
water and extracted with dichloromethane. The organic phase is
washed with water, dried on anhydrous sodium sulphate, filtered and
evaporated to dryness in vacuo. The residue is purified by flash
chromatography using a silica gel column, eluting with ethyl
acetate:methanol (95:5). The fractions containing the title product
as a base are evaporated to dryness in vacuo and one equivalent of
methanesulfonic acid dissolved in ethyl acetate is added to the
residue dissolved in ethanol. The crystallized product is filtered
and recrystallized from ethanol to give 2.4 g of the title compound
(m.p. 172.degree.-174.degree. C.).
Example 53
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl}-3-methyl-4-oxo-2-phenyl-4H-1
-benzopyran methanesulfonate
A solution of 2.8 g of the Intermediate XLVI and 0.13 g of
p-toluenesulfonic acid in 150 ml of methanol is refluxed for 5
hours. After cooling to 20.degree.-25.degree. C., 0.8 g of
anhydrous potassium carbonate is added and stirring is continued
for 3 hours. After filtration, the reaction mixture is evaporated
to dryness in vacuo to give 2.5 g of
8-(4,4-dimethoxybutyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.
NMR CDCl.sub.3 (.delta.) 1.6-1.9 (4H, m, CHCH.sub.2 CH.sub.2 CH)
2.2 (3H, s, flavone CH.sub.3) 2.9 (2H, t, Fl'-CH.sub.2) 3.3 (6H, s,
2.times.OCH.sub.3) 4.4 (1H, t, CH(OCH.sub.3).sub.2) 7.3 (1H, dd,
flavone CH in 6) 7.5-7.8 (6H, m, flavone CH in 7, and
5.times.phenyl CH) 8.1 (1H, dd, flavone CH in 5)
A solution of 2.5 g of the above compound in 10 ml of water and 30
ml of acetic acid are heated at 50.degree. C. for 2.5 hours. The
reaction mixture is cooled to ambient temperature, diluted with
iced water, basified with aqueous sodium carbonate, and extracted
with chloroform. The organic phase is dried on anhydrous sodium
sulphate, filtered and evaporated to dryness in vacuo. The residue
is purified by flash chromatography on silica gel, eluting with
petroleum ether:ethyl acetate (3:1). 2.1 g of
8-(4-oxobutyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran is obtained
(>75% yield) and is used with no further purification in the
next step.
NMR CDCl.sub.3 (.delta.) 1.9-2.1 (2H, dd, CH.sub.2 CH.sub.2
CH.sub.2 CHO) 2.2 (3H, s, flavone CH.sub.3 ) 2.5 (2H, t, CH.sub.2
CHO) 2.9 (2H, t, Fl'-CH.sub.2) 7.3 (1H, dd, flavone CH in 6)
7.5-7.7 (6H, m, flavone CH in 7, and 5.times.phenyl CH) 8.1 (1H,
dd, flavone CH in 5) 9.7 (1H, s, CHO)
2.3 ml of 6N hydrochloric acid in ethanol, a solution of 2.1 g of
the above compound in 40 ml of methanol and 0.45 g of sodium
cyanoborohydride are added in succession to a solution of 8 g of
1-(2-methoxyphenyl)piperazine in 30 ml of methanol. After stirring
the reaction at ambient temperature for 24 hours, the mixture is
poured into 500 ml of iced water and extracted with
dichloromethane. The organic phase is washed with water, dried on
anhydrous sodium sulphate and evaporated to dryness in vacuo. The
residue is purified by flash chromatography using a silica gel
column, eluting with ethyl acetate:petroleum ether (9:1). The
fractions, containing the title product as a base, are evaporated
to dryness in vacuo and an equivalent of methanesulphonic acid is
added to the residue dissolved in 30 ml of dichloromethane. The
solvent is evaporated off in vacuo and the residue is crystallized
from acetone to give 2.35 g of the title compound (m.p.
141.degree.-143.degree. C.).
Example 54
8-[3-(4-Phenyl-1-piperidinyl)propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4H-1-
benzopyran methanesulfonate
This compound is prepared by the method described in Example 11,
using 4-phenylpiperidine instead of 1-(2-methoxyphenyl)piperazine
and conducting the reaction for 1 hour instead of 5 hours.
Purification is carried out by flash chromatography using a silica
gel column, eluting with dichloromethane:methanol (100:5). m.p.
157.degree.-159.degree. C. (ethyl acetate). The respective base
melts at (127) 147.degree.-149.degree. C. (ethanol).
Example 55
8-[3-(4,4-Diphenyl-1-piperidinyl)propylcarbamoyl]-3-methyl-4-oxo-2-phenyl-4
H-1-benzopyran methanesulfonate
This compound is prepared by the method described in Example 11,
using 4,4-diphenylpiperidine instead of
1-(2-methoxyphenyl)piperazine and conducting the reaction for 2
hours instead of 5 hours. m.p. 221.degree.-223.degree. C. (ethyl
acetate).
Example 56
8-{3-[4-(4-Fluorobenzoyl)-1-piperidinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran
This compound is prepared by the method described in Example 11,
using 4-(4-fluorobenzoyl)piperidine instead of
1-(2methoxyphenyl)piperazine and conducting the reaction for 30
minutes instead of 5 hours. Purification is carried out by flash
chromatography using a silica gel column, eluting with a
dichloromethane:5N ammonia in methanol gradient (100:1 to 100:20).
m.p. 181.degree.-183.degree. C. (ethanol).
Example 57
8-{3-[4-(2-oxo-1-Benzimidazolinyl)-1-piperidinyl]-propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran
This compound is prepared by the method described in Example 11,
using 4-(2-oxo-1-benzimidazolinyl) piperidine instead of
1-(2-methoxyphenyl)piperazine. Purification is carried out by flash
chromatography using a silica gel column, eluting with chloroform:
5N ammonia in methanol (100:3). m.p. 238.degree.-241.degree. C.
(ethanol).
Example 58
8-{-[4(2-Pyrimidinyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-pheny
l-4H-1-benzopyran methanesulfonate
This compound is prepared by the method described in Example 11,
using 1-(2-pyrimidinyl)piperazine instead of
1-(2-methoxyphenyl)piperazine and conducting the reaction for 2
hours. The product is purified by flash chromatography using a
silica gel column, eluting with chloroform:methanol (100:3). The
desired fractions are dissolved in dichloromethane and an
equivalent of methanesulfonic acid is added to the solution. After
evaporation of the solvent in vacuo, the residue is boiled for 1
hour with ethyl acetate and then collected by filtration, m.p.
209.degree.-210.degree. C. The product so obtained contains 0.2
equivalents of ethyl acetate and 0.1 equivalents of water. The
respective base melts at 178.degree.-180.degree. C. (ethanol).
Example 59
8-{3-[4-(2-Hydroxyphenyl)-1-piperazinyl]propyl
carbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
Operating as described in Example 11, but using
1-(2-hydroxyphenyl)-piperazine instead of
1-(2-methoxyphenyl)piperazine, heating for 1.5 hours instead of 5
hours, and using a dichloromethane - methanol gradient (100:3 to
100:10) as eluant for column chromatography, the title compound is
obtained. m.p. 118.degree.-120.degree. C. (ethanol 95%).
Example 60
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran methanesulfonate
This compound was prepared by the method used in Example 12, but
using 4-[4-(2-methoxyphenyl)-1-piperazinyl]butylamine instead of
3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine. The reaction
mixture was stirred at room temperature for 22 hours, diluted with
water and filtered by suction, washing the insoluble solid with
water. The crude residue was dried and purified by column
chromatography on silica gel, eluting with ethyl acetate - methanol
(9:1). The fractions containing the pure product as a base were
collected, evaporated to dryness in vacuo and dissolved in
dichloromethane. Methanesulfonic acid was added to the solution and
the salt was precipitated by adding two volumes.sup.I of ethyl
acetate, filtered and recrystallized from ethanol to give the title
compound, m.p. 230.degree.-232.degree. C. This product was showed
to contain 0.3 molar equivalent of ethanol.
Example 61
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylsulfamyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran methanesulfonate
This compound was obtained operating as described in Example 12 but
using Intermediate VIII instead of
8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and
stirring for 24 hours instead of 2.5 hours. The crude was purified
by column chromatography on silica gel, eluting with ethyl acetate
- methanol (98.5:1.5). The collected fractions containing the pure
product as a base, were evaporated to dryness in vacuo and
dissolved in dichloromethane. Methanesulfonic acid was added to the
solution and the solvent was removed by evaporation in vacuo. The
crude salt was crystallized from ethanol to give the title
compound, m.p. (196) 198.degree.-200.degree. C.
Example 62
8-{3-[N-methyl-2-(2-methoxyphenoxy)-ethylamino]propylcarbamoyl}-3-methyl-4-
oxo-2-phenyl-4H-1-benzopyran hydrochloride
A solution of 10.5 ml of formaldehyde 40% in water was added to a
suspension of 6.66 g of the compound prepared in Example 14 in 55
ml of acetonitrile and 20 ml of water. After stirring for 15
minutes at room temperature, 2.70 g of sodium cyanoborohydride
(95%) was added to the red solution and after an additional 15
minutes in the same conditions, 1.38 ml of acetic acid was added.
After stirring for 3 hours, the solvents are removed in vacuo and
the residue was rinsed with 250 ml of water and 250 ml of
chloroform. After addition of 3N aqueous sodium hydroxide solution,
the organic phase was separated off and the aqueous phase was
extracted twice with chloroform. The solvent of the collected
organic phases was evaporated in vacuo and the residue was purified
by flash chromatography on silica gel, eluting with a chloroform:
5.2N methanolic ammonia gradient (100:0.5 to 100:2). The Collected
fractions containing the pure title compound as a base were
evaporated to dryness in vacuo and the residue was dissolved in hot
ethanol. The solution was acidified with ethanolic hydrogen
chloride and, after evaporation of the solvent in vacuo, the
residue was rinsed with diethyl ether and stirred at room
temperature. The crude product was collected by filtration and
crystallized from acetonitrile to give 3.1 g of the title compound,
m.p. 146.degree.-148.degree. C.
Example 63
8-{N-methyl-3-[4-(2-methoxyphenyl)-1-piperazinyl)propionamido}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran methanesulfonate
Operating as described in Example 37, but using Intermediate L
instead of Intermediate X and stirring at 90.degree. C. for 4 hours
instead of 60.degree. C. for 6 hours, the title compound was
obtained as a crude base. After purification by column
chromatography on silica gel, eluting with ethyl acetate-methanol
(95:5), a crude methanesulfonate was obtained as described in
Example 61 and crystallized from acetone to give the title
compound, m.p. 200.degree.-202.degree. C.
Example 64
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-phenyl-4-oxo-4H-
1-benzopyran dimethanesulfonate
The title compound was prepared operating as described in Example
12, but using Intermediate LVI instead of
8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and
stirring for 24 hours instead of 2.5 hours. The crude was purified
by column chromatography, eluting with ethyl acetate-methanol 92:8,
and the pure base, obtained by evaporation in vacuo of the
collected fractions, was dissolved in dichloromethane and added
with two equivalents of methanesulfonic acid. The crude
dimethanesulfonate, obtained after evaporation of the solvent, was
recrystallized from acetone, m.p. (153-156) 200.degree. C.
Example 65
8-{3-[2-(3,4-Dihydro-1,
(2H)-naphthalenonyl)methylaminolpropyl-carbamoyl}-3-methyl-4-oxo-2-phenyl-
4H-1-benzopyran methanesulfonate
A mixture of 6 g of Intermediate XLIII, 2.4 g of
2-methylene-.alpha.-tetralone [prepared as described in Org.
Synth., 60, 88 (1981)] and 3.14 ml of triethylamine in 48 ml of
anhydrous dimethylformamide was stirred at room temperature for 6
hours, then at 50.degree. C. for additional 1 hour. The reaction
mixture was diluted with water and extracted with dichloromethane.
The organic layers were washed with water, dried on anhydrous
sodium sulfate and evaporated to dryness in vacuo. The crude
residue was purified twice by column chromatography eluting firstly
with dichloromethane - methanol (95:5) and then with
dichloromethane methanol - 5.8N methanolic ammonia (98:2:0.2), to
give 1.74 g of the title compound as a base. The base was converted
into the methanesulfonate by the procedure described in Example 61.
The salt was recrystallized first from acetone and then from
acetonitrile to give the title compound, m.p. (69)
157.degree.-159.degree. C.
Example 66
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethoxycarbonylmethyl}-3-methyl-4-ox
o-2-phenyl-4H-1-benzopyran dihydrochloride
The title compound was prepared by the method described in Example
5, but using Intermediate XLVII in place of
8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and
1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine instead of
1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine. m.p.
193.degree.-196.degree. C. from ethanol/diethyl ether.
Example 67
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butylsulfamyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran dimethanesulfonate
The title compound was prepared as described in Example 61 but
using 4-[4-(2-methoxyphenyl)-1-piperazinyl]butylamine instead of
3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine. The crude
dimethanesulfonate was crystallized first from acetonitrile and
then from ethanol, m.p. 172.degree.-174.degree. C.
Example 68
8-{N,2-tetrahydropyranyloxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarb
amoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate
hemihydrate
A solution of 3.6 g of
1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine in 30 ml of
anhydrous dimethylformamide was added dropwise, under stirring at
0.degree. C., to a mixture of 3.92 g of 0,2-tetrahydropyranyl
hydroxylamine [prepared as described by R. N. Watrener et al.,
Angewandte Chem. Int. Ed., 5, 511 (1966)] and 9.2 g of anhydrous
potassium carbonate in 100 ml of DMF. Stirring at 0.degree. C. was
continued for 2 hours, and then for 12 hours at 110.degree. C. The
reaction mixture was cooled to room temperature and
dimethylformamide removed by distillation in vacuo. The residue was
rinsed with water and extracted with ethyl acetate. The combined
organic layers were washed with water, dried on anhydrous sodium
sulfate and the solvent was evaporated to dryness in vacuo to give
4.39 g of
1-[3-(2-tetrahydropyranyloxyamino)propyl]-4-(2-methoxyphenyl)piperazine.
1H-NMR (CDCl3; (.delta.)) 6.50-6.75 (m; 4H) aromatic protons 5.20
(bs; 1H) NH 4.60 (m; 1H) O--CH--O 3.30-4.00 (m; 5H) OCH.sub.3 and
tetrahydropyran CH.sub.2 O 2.80-3.20 (m; 6H) piperazine
2.times.CH.sub.2 alkyl chain CH.sub.2 N 2.20-2.80 (m; 6H)
piperazine 2.times.CH.sub.2, alkyl chain CH.sub.2 N 1.30-2.00 (m;
8H) tetrahydropyran 3.times.CH.sub.2, alkyl chain C-CH.sub.2 C
A solution of 2.79 g of
8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 47 ml
of chloroform was added dropwise at room temperature to a mixture
of 3.26 g of the above-described Intermediate and 1.42 g of
potassium carbonate in 47 ml of chloroform. The reaction mixture
was stirred for 3 hours, then diluted with 75 ml of chloroform and
washed three times with 1M aqueous sodium hydroxide solution; the
organic layer was washed with water, dried on anhydrous sodium
sulfate and evaporated to dryness in vacuo. The crude residue was
purified by column chromatography on silica gel eluting with ethyl
acetate - methanol (98:2). The collected fractions were evaporated
to dryness in vacuo to give 2.99 g of pure title compound as a
base, which was dissolved in dichloromethane. Methanesulfonic acid
was added to the solution and the solvent was removed by
evaporation in vacuo. The crude salt was crystallized from ethyl
acetate to yield the title compound, m.p. 159.degree.-160.degree.
C.
Example 69
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyramido}-3-methyl-4-oxo-2-phenyl
-4H-1-benzopyran methanesulfonate hemihydrate
The title compound was prepared operating as described in Example
38, but using Intermediate XLVIII instead of Intermediate XLIV and
stirring 1 hour at 70.degree. C. and 2 hours at 130.degree. C.
instead of 7 hours at 100.degree. C. After the usual workup, the
crude residue was purified by column chromatography on silica-gel
eluting with ethyl acetate - methanol (95:5). The fractions
containing the pure title compound as a base were collected and
evaporated to dryness in vacuo. The residue was dissolved in
methylene chloride and one equivalent of methanesulfonic acid was
added to the solution. After evaporation of the solvent to dryness
in vacuo, the crude salt was crystallized from acetone, m.p.
175.degree.-176.degree. C.
Example 70
E-8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethoxyaminomethyl}-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran
A solution of 5.4 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 5.13 g of
Intermediate LII in 10 ml of chloroform, containing molecular
sieves 3A, was stirred at reflux for 6 hours. Molecular sieves were
removed by filtration and the solvent evaporated to dryness in
vacuo. The crude product was purified by column chromatography on
silica gel, eluting with ethyl acetate - petroleum ether (7:3); two
groups of fractions were collected and the solvent evaporated in
vacuo. The first eluted group of fractions (less polar) containing
almost pure title compound; the second group (more polar) was a 1:1
mixture of the E and Z diastereomers, as determined as by 1H-NMR at
200 MHz.
1H-NMR (CDCl3, (.delta.)) 8.75 (dd, 0.5H) benzopyran CH in 7 (Z)
8.65 (s, 0.4H) iminic CH (E) 8.30 (dd, 1H) benzopyran CH in 5 (E+Z)
8.15 (dd, 0.5H) benzopyran CH in 7 (E) 8.00 (s, 0.5H) iminic CH (Z)
7.60-7.75 (m, 2H) phenyl CH in 2' and 6' (E+Z) 7.50-7.60 (m, 3H)
phenyl CH in 3', 4' and 5' (E+Z) 7.45 (dd, 0.5H) benzopyran CH in 6
(Z) 7.41 (dd, 0.5H) benzopyran CH in 6 (E) 6.70-7.10 (m, 4H) phenyl
protons (E+Z) 4.41 (t, 2H) CH.sub.2 O (E+Z) 3.86 (s, 3H) CH.sub.3 O
(E+Z) 3.05-3.20 (m, 4H) piperazine 2.times.CH.sub.2 (E+Z) 2.70-2.90
(m, 6H) piperazine 2.times.CH.sub.2 and CH.sub.2 N (E+Z) 2.20 (s,
1.5H) benzopyran CH.sub.3 in 3 (Z) 2.18 (s, 1.5H) benzopyran
CH.sub.3 in 3 (E)
The E diastereoisomer was crystallized from ethanol-water 2:1 to
give 2.5 g of pure title compound, m.p. 107.degree.-109.degree.
C.
Example 71
8-{N-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl-carbamoyl}-3-meth
yl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.times.0.25
H.sub.2 O
A solution of 2.04 g of compound of Example 68 as a base in 104 ml
of 1.6N ethanolic hydrochloric acid was stirred for 12 hours at
room temperature. Ethanol was removed by evaporation in vacuo and
the residue was rinsed with 1N aqueous sodium hydroxide solution
and dichloromethane. The organic layer was collected, washed with
water, dried on anhydrous sodium sulfate and evaporated to dryness
in vacuo. One molar equivalent of methanesulfonic acid was added to
a solution of the residue in dichloromethane. The solvent was
removed and the crude methanesulfonate crystallized from acetone to
give 1.02 g of the title compound, m.p. 211.degree.-213.degree. C.
The product contained 0.25 mole of water.
Example 72
E-8-{2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylcarbamoyl}-ethenyl}-3-met
hyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate.times.1.2
H.sub.2 O
The title compound was obtained operating as described in Example
61 but using Intermediate IV instead of Intermediate VIII and
2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamine instead of the
corresponding propylamine, in 1,1,2,2,-tetrachloroethylene as
solvent. At the end, the reaction mixture was diluted with water
and chloroform and washed with 1N aqueous sodium hydroxide
solution, then with water. To the organic layer, after drying on
anhydrous sodium sulfate, was added methanesulfonic acid and the
solvents were evaporated to dryness in vacuo. The crude product was
crystallized twice from isopropanol to give the title compound
containing 1.2 molar equivalent of water (m.p.
124.degree.-127.degree. C.).
Example 73
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butylsulfinyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran methanesulfonate
The title compound was prepared according to Example 38, but using
Intermediate LIV instead of Intermediate XLIV, stirring at
70.degree. C. for 3 hours and again at 90.degree. C. for 3 hours
after adding catalytic quantity of potassium iodide (0.01
equivalents). Purification by column chromatography on silica gel,
eluting with ethyl acetate - methanol (9:1), gave the title
compound as base. To the crude base, dissolved in dichloromethane,
was added one molar equivalent of methanesulfonic acid. After
removal of the solvent by evaporation in vacuo, the resulting saint
was crystallized from acetone to give the title compound (m.p.
183.degree.-184.degree. C.).
Example 74
8-{3-[3-(2-Methoxyphenoxy)propylamino]propylcarbamoyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran methanesulfonate hemihydrate
The title compound was prepared according to the method described
in Example 76 but using 3-(2-methoxyphenoxy)propyl chloride
(prepared as described in B. Willhalm, Tetrahedron, 20, 1185,
(1964)) instead of 2-(2,6-dimethoxyphenoxy) ethyl bromide. The
residue from dichloromethane extraction was purified by column
chromatography on silica gel eluting with
dichloromethane-methanol-5N methanolic ammonia (9:1:0.3); the pure
base was converted into the methanesulfonate, which was
crystallized twice from ethyl acetate-acetonitrile (9:1) to give
the title compound, melting at (60) 87.degree.-90.degree. C.
Example 75
3-Methyl-8-{3-[2-(2-methylthiophenoxy)ethylamino]propyl
carbamoyl}-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 0.75
H.sub.2 O
1.85 g of 95% sodium borohydride was added to a solution of 7 g of
Intermediate LIX in 70 ml of methanol stirred at 0.degree. C. After
1 hour stirring at the same temperature, the solvent was removed by
evaporation in vacuo; the residue was diluted with water and 2N
aqueous hydrochloric acid solution and extracted with ethyl
acetate. The organic layer was washed with water, dried on sodium
sulfate and evaporated to dryness in vacuo, giving 6.6 g of pure
2-(2-methylthiophenoxy)ethanol as an oil. 8.57 g of
p-toluenesulfonyl chloride was added portionwise to a solution of
the above Intermediate in 35 ml of pyridine stirred at 0.degree.
C.
After 14 hours stirring at room temperature, the reaction mixture
was poured into cold 2N aqueous hydrochloric acid solution and
extracted with dichloromethane; the organic layer was washed twice
with water, dried on sodium sulfate and evaporated to dryness in
vacuo yielding 7.8 g of a 3:1 mixture of
2-(2-methylthiophenoxy)ethyl p-toluenesulfonate and
1-chloro-2-(2-methylthiophenoxy)ethane (assessed by NMR) as a low
melting solid which was used without further purification.
A homogeneous mixture of 3.3 g of the above mixture and 8 g of the
Intermediate XLIII was kept in an oil bath at 140.degree. C. for 20
minutes. After this period the melted mass was cooled to room
temperature and solidified. The solid residue was rinsed with
dichloromethane and 4N aqueous sodium hydroxide solution; the
organic layer was washed with water, dried on sodium sulfate and
evaporated to dryness in vacuo.
The crude was purified by column chromatography on silica gel
eluting with dichloromethane-methanol (9:1) giving 2.07 g of the
title compound as a base. This was converted by the usual method
into a crude methanesulfonate, which was crystallized firstly from
acetone, then from acetonitrile and melted at
143.degree.-146.degree. C.
Example 76
8-{3-[2-(2,6-Dimethoxyphenoxy)ethylamino]propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran hydrochloride
A homogeneous mixture of 3.3 g of 2-(2,6-dimethoxyphenoxy)ethyl
bromide (prepared as described in J. Augstein et al., J. Med.
Chem., 8, 356 (1965)) and 8.4 g of Intermediate XLIII was heated in
an oil bath at 150.degree. C. for 10 minutes.
The melted mass was cooled to room temperature and solidified; the
solid residue was rinsed with ethyl acetate and 2N sodium
hydroxide; the organic layer was washed with water, dried on sodium
sulfate and evaporated to dryness in vacuo. The oily residue was
purified twice by column chromatography on silica gel eluting
firstly with ethyl acetate-methanol-5N methanolic ammonia
(97:3:0.3) then with dichloromethane-methanoltriethylamine
(90:10:0.3) yielding 3.3 g of pure title compound. The crude
hydrochloride obtained by the usual method, was crystallized from
acetone followed by acetonitrile (m.p. 179.degree.-181.degree.
C.).
Example 77
8-{3-[4-(5-Chloro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran
This compound was prepared by the method described in Example 11,
but using 1-(5-chloro-2-methoxyphenyl-piperazine instead of
1-(2-methoxyphenyl)piperazine and carrying out the reaction for 6
hours instead of 5 hours. Purification was carried out by flash
chromatography on silica gel, eluting with chloroform: 5N ammonia
in methanol (100:1). The title compound melted at
163.degree.-166.degree. C. after crystallization from 95%
ethanol.
Example 78
(E)-8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]-1-butenyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran
33.4 ml of a 1 molar solution of lithium bis(trimethylsilyl)amide
in anhydrous tetrahydrofuran was added dropwise during 15 minutes
to a suspension of 6.4 g of 3-hydroxypropyltriphenylphosphonium
bromide in 60 ml of anhydrous tetrahydrofuran cooled to -15.degree.
C.
Thereafter, a solution of 4 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 40 ml of
tetrahydrofuran was added dropwise. The reaction mixture was
stirred at 0.degree. C. for 0.5 hour, then at room temperature for
1.5 hours.
Quenching with methanol, followed by evaporation to dryness in
vacuo of the solvents gave a residue which was purified by column
chromatography on silica gel using a mixture of ethyl
acetate-petroleum ether (6:4). The collected fractions were
evaporated in vacuo giving 4.17 g of
8-(4-hydroxy-1-butenyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran as
a E-Z diastereomers mixture having a 3.5:1 ratio, determined by
1H-NMR spectroscopy at 200 MHZ.
1H-NMR (CDCl.sub.3, (.delta.)) 8.10-8.20 (d,1H) benzopyran CH in 5
(E+Z) 7.30-7.80 (m,7H) other aromatics (E+Z) 6.80; 7.00 (2d, 1H)
aryl--CH.dbd.(E+Z) 6.41 (dt,0.78H) CH--CH.sub.2 (E) 5.90 (dt,0.22H)
CH--CH.sub.2 (Z) 3.60-3.80 (m,2H) CH.sub.2 O (E+Z) 2.45-2.60 (m,2H)
CH--CH.sub.2 (E+Z) 2.18 (s,3H) benzopyran CH.sub.3 in 3 (E+Z)
1.60-1.90 (sa,1H) OH (E+Z)
1.65 g of p-toluenesulfonyl chloride was added to a solution of 2.2
g of the above mixture in 24 ml of anhydrous pyridine stirred at
0.degree. C. Stirring was continued for 48 hours at the same
temperature, then the reaction mixture was poured into cold 1N
aqueous hydrochloric acid solution and filtered by suction. The
gummy solid was washed with water and rinsed with dichloromethane.
The solution was dried on sodium sulfate and evaporated to dryness
in vacuo to give 2.30 g of
(E,Z)-4-{8-[3-methyl-4-oxo-2-phenyl-4H-1-benzopyranyl}-3-butenyl
p-toluenesulfonate having the same diastereoisomer composition as
the above Intermediate.
A solution of 2.85 g of the p-toluenesulfonic acid ester above and
of 2.98 g of 1-(2-methoxyphenyl)piperazine in anhydrous
dimethylformamide was stirred at room temperature for 48 hours.
After this period, the mixture was poured into 250 ml of water and
extracted with ethyl acetate.
The organic layer was washed with water, dried on sodium sulfate
and evaporated to dryness in vacuo giving a residue which was
purified by column chromatography on silica gel eluting with ethyl
acetate-petroleum ether 6:4. The collected fractions were
evaporated to dryness in vacuo and the crude was crystallized from
70% ethanol yielding 1.48 g of the title compound that melted at
119.degree.-121.degree. C.
1H-NMR spectrum at 200 MHz (CDCl.sub.3, (.delta.)) 8.14 (dd,1H)
benzopyran CH in 5 7.85 (dd,1H) benzopyran CH in 7 7.41-7.70 (m,5H)
phenyl CHs 7.34 (dd,1H) benzopyran CH in 6 6.70-7.10 (m,5H) aryl -
CH.dbd. and methoxyphenyl CHs 6.30-6.50 (dt, 1H, J.sub.trans =16.5
Hz) CH-CH.sub.2 3.86 (s,3H) CH.sub.3 O 3.00-3.15 (m,4H) 2
piperazine CH.sub.2 2.50.degree.-2.80 (m,8H) 2 piperazine CH.sub.2,
CHCH.sub.2 CH.sub.2 N 2.18 (s,3H) benzopyran CH.sub.3 in 3
Example 79
(E)-8-{2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethoxycarbonyl]ethenyl}-3-me
thyl-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate
The title compound was prepared according to Example 6, but using
Intermediate III instead of
8-carboxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.
After the usual workup, the residue was crystallized twice from
ethanol; the solid obtained was purified by column chromatography
on silica gel eluting with chloroform-ethyl acetate (8:2) to give
the pure base, which was dissolved in chloroform-ethyl alcohol
(1:1). Methanesulfonic acid was added to the solution and the
solvents were removed by evaporation in vacuo. The crude salt was
crystallized from isopropyl alcohol yielding the title compound,
melting at 193.degree.-195.degree. C. This compound contained 0.33
equivalents of isopropanol and 0.25 equivalents of water.
Example 80
8-{{2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethylcarbamoyl}methyl}-4-oxo-2-phe
nyl-4H-1-benzopyran methanesulfonate hydrate
A mixture of 2.8 g of Intermediate XLVII and 1.28 g of
1-hydroxybenzotriazole in 20 ml of anhydrous dimethylformamide was
stirred ar 0.degree./5.degree. C. for 15 minutes and added
dropwise, in about 40 minutes, with a solution of 1.96 g of
dicyclohexylcarbodiimide in 20 ml of anhydrous dimethylformamide.
After 8 hours stirring at room temperature, a solution of 2.24 g of
1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine in 15 ml of
anhydrous dimethylformamide was added.
After 5 hours stirring and overnight standing at the same
temperature, the insoluble was filtered and the filtrate was poured
into about 300 ml of water and made alkaline by addition of 1N
aqueous sodium hydroxide solution. The mixture was extracted with
dichloromethane and the organic layer was separated, dried on
anhydrous sodium sulfate and evaporated in vacuo. The crude was
purified by flash chromatography on silica gel eluting with a
mixture of chloroform-methanol (95:5). One molar equivalent of
methanesulfonic acid was added to the solution of the crude base in
ethanol, followed by diethyl ether until crystallization of the
salt. This one was filtered and recrystallized from a 1:2 mixture
of ethanol and diethyl ether to give 1.15 g of the title compound,
m.p. 160.degree.-162.degree. C.
Example 81
8-{N-acetyl-N-3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methy
l-4-oxo-2-phenyl-4H-1-benzopyran
A solution of 2.86 g of Intermediate LVII, 5.04 g of
1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine and 2.58 g of
anhydrous potassium carbonate in 50 ml of dimethylformamide was
stirred at 90.degree. C. for 7 hours. After cooling to room
temperature, the reaction mixture was poured into 500 ml of water
and extracted with dichloromethane; the organic layer was washed
with water, dried on sodium sulfate and evaporated to dryness in
vacuo.
The residue was purified by column chromatography on silica gel
eluting with ethyl acetate-petroleum ether (7:3) to give 1.89 g of
the title compound melting at (55) 62.degree.-63.degree. C.
Example 82
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethylsulfonylamino}-3-methyl-4-oxo-
2-phenyl-4H-1-benzopyran methanesulfonate
1.05 ml of 2-chloroethanesulfonyl chloride was added dropwise to a
solution of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
and 1.4 ml of triethylamine stirred at 0.degree. C. The reaction
mixture was stirred at room temperature for 2 days. After filtering
the precipitated solid, the solution was evaporated to dryness in
vacuo to give a crude residue containing
8-(ethenYlsulfonylamino)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
used without further purification. A mixture of 7.54 g of this
residue and 5.8 g of 1-(2-methoxyphenyl)piperazine and 4.15 g of
potassium carbonate in 100 ml of dimethylformamide was stirred at
room temperature for 4 hours, poured into 600 ml of water and
extracted with ethyl acetate. The organic layer was evaporated to
dryness in vacuo and the residue was purified-by column
chromatography on silica gel eluting with petroleum ether-acetone
8:2. The collected fractions were evaporated to dryness in vacuo
and crystallized from 70% ethanol to give 0.75 g of the title
compound as a base. This solid was dissolved in dichloromethane and
1 equivalent of methanesulfonic acid was added to the solution. The
crude methanesulfonate, obtained by evaporation in vacuo, was
crystallized from acetone, yielding 0.6 g of the title compound
melting at 202.degree.-203.degree. C.
Example 83
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylthiocarbamoyl}-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran methanesulfonate
A stirred mixture of 0.8 g
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 0.75 g of
1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine and 0.14 g of
sulfur in 5 ml of pyridine was refluxed for 6 hours.
After solvent evaporation in vacuo, the residue was purified by
flash chromatography on silica gel, eluting with chloroform. The
obtained title compound (as the base) was dissolved in
dichloromethane and added with an equivalent of methanesulfonic
acid. The title compound was obtained by evaporation in vacuo and
crystallization of the residue from acetonitrile. Yield 0.7 g, m.p.
189.degree.-190.degree. C.
Example 84
8-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butylsulfonyl}-3-methyl-4-oxo-2-phe
nyl-4H-1-benzopyran methanesulfonate - 0.25 H.sub.2 O
The title compound was prepared according to Example 73, but using
Intermediate LX instead of Intermediate LIV. Its purification was
performed by column chromatography on silica gel, eluting with
ethyl acetate-petroleum ether (7:3). One molar equivalent of
methanesulfonic acid was added to a solution of the crude base in
dichloromethane.
After removal of the solvent by evaporation in vacuo, the resulting
salt was crystallized from acetone to give the title compound, m.p.
212.degree.-214.degree. C.
Example 85
3-Hydroxymethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl
carbamoyl}-4-oxo-2-phenyl-4H-1-benzopyran. 0.4 ethanol
A mixture of 3.6 g of Intermediate XCV and 1.65 g of
1-hydroxybenzotriazole in 35 ml of anhydrous dimethylformamide was
stirred at 0.degree./5.degree. C. for 15 minutes and added dropwise
with a solution of 2.5 g of dicyclohexylcarbodiimide in 35 ml of
anhydrous dimethylformamide. After 1 hour stirring at the same
temperature, a solution of
1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine was added.
After 2 hours stirring at the same temperature and overnight
standing at room temperature, the reaction mixture was evaporated
to dryness in vacuo. The residue was purified by flash
chromatography eluting with a mixture of dichloromethane-methanol
(100:3), followed by crystallization from ethanol. 2.5 g of the
title compound was obtained, m.p. 152.degree.-154.degree. C.
Example 86
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-phenyl-4H-
1-benzopyran methanesulfonate. 0.25 H.sub.2 O
3.6 ml of diethyl cyanophosphonate were added dropwise at
0.degree./5.degree. C. into a stirred solution of 4 g of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid (prepared as
described in Da Re et al., Ber., 99, 1962 (1966)) and 3.75 g of
1-(3-aminopropyl)-4-(2methoxyphenyl)piperazine in 35 ml of
anhydrous dimethylformamide. Immediately afterwards, 2.5 ml of
triethylamine was added dropwise at the same temperature. After 30
minutes stirring at 0.degree./5.degree. C. and 1 hour at room
temperature, the reaction mixture was poured into 350 ml of 2.5%
aqueous sodium carbonate solution. The precipitate formed was
stirred for 1 hour at room temperature, collected by suction and
crystallized from ethanol. The title compound obtained in this way
as the base was dissolved in dichloromethane and added with one
equivalent of methanesulfonic acid. After evaporation in vacuo, a
glassy solid was obtained, which was crushed and refluxed for 1
hour in acetone, yielding 5 g of the title compound melting at
191.degree.-194.degree. C.
Example 87
2,3-Dihydro-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-
4H-1-benzopyran methanesulfonate
A solution of 0.84 ml of thionyl chloride in 17 ml of anhydrous
dichloromethane was added dropwise to a solution of 2.0 g of
2,3-dihydro-4-oxo-4H-1-benzopyran-8-carboxylic acid (prepared as
described in Lichtenberger et al., Bull. Chem. Soc. Fr., 275
(1963)) and 1.75 ml of triethylamine in 17 ml of dichloromethane
stirred at room temperature.
Stirring was continued for 1.5 hour at the same temperature; after
this period the reaction mixture was evaporated to dryness in vacuo
giving 8-chlorocarbonyl-2,3-dihydro-4-oxo-4H-1-benzopyran as a
crude.
Using the above Intermediate instead of
8-chlorocarbonyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, the title
compound was prepared according to Example 10. The crude was
purified by column chromatography eluting with ethyl
acetate-methanol (85:15) yielding 1.91 g of the pure base, which
was dissolved in dichloromethane and converted into its
methanesulfonate salt by addition of methanesulfonic acid. This
solution was evaporated to dryness in vacuo and the crude salt was
crystallized from acetonitrile giving 1.57 g of the title compound
(m.p. 175.degree.-177.degree. C.).
Example 88
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-4H-1-benzopy
ran methanesulfonate 1.25 H.sub.2 O
The title compound was prepared by the method described in Example
87, but using Intermediate LXII instead of
2,3-dihydro-4-oxo-4H-1-benzopyran-8-carboxylic acid.
The crude methanesulfonate was rinsed with diethyl ether, filtered
and repeatedly crystallized from acetonitrile (m.p.
155.degree.-157.degree. C.).
Example 89
6-Bromo-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4
-oxo-2-phenyl-4H-1-benzopyran
This compound was prepared according to Example 86, but using
6-bromo-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
(prepared as described in EP 107804 (1983)) instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. It was purified
as a base by flash chromatography on silica gel eluting with
dichloromethane-methanol (100:3), and crystallized from 95% ethanol
(m.p. (150) 154.degree.-159.degree. C.).
Example 90
6-Methoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate
1.01 ml of diethylcyanophosphonate and 0.85 ml of triethylamine
were added to a solution of 1.7 g of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
(prepared as described in JP 61.degree.-15880) and 1.51 g
1-(2-methoxyphenyl)-4-(3aminopropyl)piperazine in 20 ml of
anhydrous dimethylformamide stirred at 0.degree. C.
After 1 hour stirring at 0.degree. C. to room temperature, the
reaction mixture was poured into a mixture of 100 ml of water and
10 ml of 1N aqueous sodium hydroxide solution. The title compound
precipitated as a base and was filtered and washed with water.
After desiccation it was converted in the usual way to the
methanesulfonate, which was crystallized from acetonitrile yielding
1.7 g melting at 185.degree.-186.degree. C.
Example 91
6-Hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate
0.8 g of compound of Example 114 and 5.8 ml of 1N sodium hydroxide
in 10 ml of methanol was stirred at room temperature for 4
hours.
After standing overnight, 15 ml of 1N sodium hydroxide and 15 ml of
methanol was added and the mixture was stirred at room temperature
for 1 hour. Methanol was evaporated in vacuo and water was added to
the residue. The suspension was filtered by suction to give 0.48 g
of the title compound as a base which was converted by the usual
procedure into its methanesulfonate salt, recrystallized from
acetonitrile (m.p. 200.degree.-202.degree. C.).
Example 92
3,6-Dimethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl
carbamoyl}-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate
The title compound was prepared according to Example 90 but using
3,6-dimethyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
(prepared as described in Da Re et al., Arch. Pharm., 296, 714
(1963)) instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid.
The crude methanesulfonate was crystallized from acetonitrile (m.p.
196.degree.-197.degree. C.).
Example 93
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-6-nitro-4
-oxo-2-phenyl-4H-1-benzopyran
This product was obtained operating as described in Example 12 but
using Intermediate LXVIII instead of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and
1,1,2-trichloroethane instead of chloroform.
After the usual workup, the crude was purified by column
chromatography eluting with dichloromethane-methanol 98:2.
Evaporation in vacuo to dryness of the collected fractions and
crystallization from ethanol yielded the title compound (m.p.
159.5.degree.-161.degree. C.).
Example 94
6-Amino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl
carbamoyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
A mixture of 33 g of compound of Example 93, 109 ml of 1N
hydrochloric acid, 105 ml of water and 8.78 g of Raney-Ni in 950 ml
of ethanol was hydrogenated in a Parr apparatus (PH.sub.2 =2 atm)
stirring at 40.degree. C. for 12 hours. After this period, the
catalyst was filtered off and washed with 80% ethanol. The mother
liquors were evaporated in vacuo, reaching a volume of 80 ml and
filtered, washing the crude with water.
The crude was suspended in water; 37% hydrochloric acid was added
up to pH=1. The insoluble was filtered by suction and the filtrate
was alkalinized by adding 35% aqueous sodium hydroxide solution.
The title compound that precipitated was recovered by filtration
and washed with water. Desiccation yielded 26 g melting at (108)
215.degree.-217.5.degree. C. This compound was used as an
Intermediate without further purification. 4.7 g were crystallized
firstly from ethanol and then from 85% ethanol, to give 3 g of the
title compound (m.p. 218.degree.-219.degree. C.).
Example 95
6-Acetylamino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-2-phenyl-4H-1-benzopyran
The title compound was obtained according to the procedure
described in Example 36, but using the compound prepared in Example
94 instead of that one of Example 33. The reaction mixture was
diluted with water and filtered by suction, washing the solid with
water. After desiccation at 80.degree. C., this solid was purified
by column chromatography on silica gel eluting with
chloroform-methanol (95:5). Evaporation in vacuo of the collected
fractions and crystallization from 95% ethanol of the residue gave
the title compound, m.p. (150) 218.degree.-220.degree. C.
Example 96
6-Ethylamino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-2-phenyl-4H-1-benzopyran
A mixture of 8.42 g of the compound of Example 94, 0.45 ml of
acetaldehyde, 0.59 g of 85% sodium cyanoborohydride and 3.3 ml of
4.85N ethanolic hydrochloric acid in 73 ml of methanol was stirred
at room temperature for 5 days.
After this period, the reaction mixture was poured into cold 1.5N
sodium hydroxide; the suspension was diluted with water and
filtered by suction. After desiccation, the residue was purified by
column chromatography on silica gel eluting with
chloroform-methanol 100:3. Evaporation in vacuo of the collected
fractions yielded 6 g of the compound of Example 94 and 2.67 g of
the title compound, which melted at 198.degree.-201.degree. C.,
after recrystallization from ethanol.
Example 97
6-Dimethylamino-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-
methyl-4-oxo-2-phenyl-4H-1-benzopyran
The title compound was prepared according to Example 35, but using
the compound prepared in Example 94 instead of that prepared in
Example 33, reacting 10 molar equivalents of 40% formaldehyde
instead of 7 molar equivalents and 3 moles of sodium
cyanoborohydride instead of 2 moles and stirring at room
temperature for 18 hours instead of 4.5 hours. After the usual
workup, the crude was purified by column chromatography on silica
gel eluting with chloroform-methanol 97:3. Evaporation in vacuo of
the collected fractions and crystallization of the residue from
ethanol yielded the title compound which melted at
183.degree.-186.degree. C.
Example 98
7-Methoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran
The title compound was prepared according to the procedure
described in Example 87, but using Intermediate LXIX instead of
2,3-dihydro-4-oxo-4H-1-benzopyran-8-carboxylic acid. After the
usual workup, the solid residue was purified by column
chromatography on silica gel eluting with ethyl acetate-methanol
(8:2). The collected fractions were evaporated to dryness in vacuo
and the residue was crystallized from acetonitrile to give the
title compound, melting at 151.degree.-152.degree. C.
Example 99
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
4-trifluoromethylphenyl)-4H-1-benzopyran methanesulfonate 1.5
H.sub.2 O
The title compound was prepared following the procedure described
in Example 90 starting from Intermediate LXXII instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The methanesulfonate melted at (85) 90.degree.-120.degree. C.
with decomposition, after crystallization from acetonitrile.
Example 100
2-(4-Benzoylphenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl
}-3-methyl-4-oxo-4H-1-benzopyran methanesulfonate hemihydrate
The title compound was prepared following the procedure described
in Example 90, but starting from Intermediate LXXIV instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The crude methanesulfonate was crystallized from acetonitrile
and melted at 208.degree.-210.degree. C.
Example 101
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
4-phenoxyphenyl)-4H-1-benzopyran methanesulfonate. 0.25 H.sub.2
O
The title compound was prepared following the procedure described
in Example 90 but starting from Intermediate LXXVII instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The crude methanesulfonate was crystallized from
acetonitrile, m.p. 200.degree.-202.degree. C.
Example 102
2,3-Dimethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo
-4H-1-benzopyran
This compound was prepared according to Example 86, but using
2,3-dimethyl-4-oxo-4H-1-benzopyran-8-carboxylic acid (prepared as
described in Da Re, Farmaco Ed. Sci., 11, 678 (1956)) instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and carrying out
the reaction at room temperature for 5 hours. It was purified as a
base by flash chromatography on silica gel eluting with
chloroform-methanol (98:2), and crystallized from acetone (m.p.
155.degree.-158.5.degree. C.).
Example 103
2-tert-Butyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-4H-1-benzopyran dihydrochloride dihydrate
This compound was prepared according to Example 86, but using
Intermediate LXXVIII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid.
The base was purified by flash chromatography on silica gel eluting
with a mixture of chloroform-methanol (49:1) and converted into the
dihydrochloride in methanol-diethyl ether. It melted at
226.degree.-229.5.degree. C. after recrystallization from
methanol-diethyl ether (1:1).
Example 104
2-Cyclohexyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-met
hyl-4-oxo-4H-1-benzopyran
This compound was prepared according to Example 86, but using
Intermediate LXXIX instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, and carrying out
the reaction for 5 hours at room temperature.
It was purified as a base by flash chromatography on silica gel
eluting with a mixture chloroform-methanol (49:1), and crystallized
from acetonitrile (m.p. 155.degree.-157.degree. C.).
This compound was also isolated as its monomethanesulfonate salt by
addition of one equivalent methanesulfonic acid to a solution of
the base in boiling ethanol, cooling to ambient temperature, and
filtering. Recrystallization from ethanol provided the pure
product, m.p. 210.degree.-211.degree. C.
Example 105
2-(2-Furyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-meth
yl-4-oxo-4H-1-benzopyran
This compound was prepared according to Example 86 but using
Intermediate LXXXI instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, and completing
the reaction at room temperature for 5 hours. After quenching, the
title compound was isolated by extraction with chloroform and
purified by flash chromatography on silica gel eluting with the
mixture chloroform-methanol 49:1, followed by crystallization from
acetonitrile (m.p. 151.degree.-153.degree. C.).
Example 106
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-t
hienyl-4H-1-benzopyran
This compound was obtained according to Example 86, but using
Intermediate LXXXIII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. It was purified
by stirring in water (to completely remove dimethylformamide),
followed by column chromatography on silica gel eluting with the
mixture chloroform-methanol (49:1), and crystallized from
acetonitrile (m.p. 174.degree.-175.degree. C.).
Example 107
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-phenyl-4H-
1-benzothiopyran
A mixture of 2.8 g of Intermediate LXXXIV and 3.4 g of
1,1-carbonyldiimidazole in 60 ml of anhydrous dimethylformamide was
stirred under N.sub.2 at room temperature for 1.5 hours.
Afterwards, 2.7 g of
1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine was added. After
further 2 hours stirring at room temperature, the reaction mixture
was poured into 300 ml of water and extracted with chloroform. The
organic layer was dried on anhydrous sodium sulfate and evaporated
in vacuo. The residue was purified by flash chromatography on
silica gel eluting with chloroform-methanol (49:1), washed with
water and crystallized from acetonitrile, yielding 2 g of the title
compound melting at 144.degree.-146.degree. C.
Example 108
(E)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo
-2-(2-phenylethenyl)-4H-1-benzopyran
This compound was prepared according to Example 86, but using
Intermediate LXXXVI instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. It was purified
by crystallization from acetonitrile (m.p. 191.degree.-194.degree.
C.).
Example 109
8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(4-meth
ylphenyl)-4-oxo-4H-1-benzopyran
This compound was prepared according to Example 86, but using
Intermediate LXXXVII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid and completing the
reaction at room temperature for 4 hours.
After quenching, the title compound was isolated by extraction with
ethyl acetate, drying on sodium sulfate and evaporation in vacuo,
followed by rinsing with diethyl ether and crystallization from
acetonitrile (m.p. 161.degree.-163.degree. C.).
Example 110
2-(4-Methoxyphenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl
}-3-methyl-4-oxo-4H-1-benzopyran
This compound was prepared according to Example 86, but using
2-(4-methoxyphenyl)-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic
acid (prepared as described in EP 108986 (1984)) instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, and completing
the reaction at room temperature for 3.5 hours. It was purified by
flash chromatography on silica gel eluting with chloroform-methanol
(49:1), followed by crystallization from acetonitrile (m.p.
158.degree.-161.degree. C.).
Example 111
2-(4-Fluorophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl
carbamoyl}-3-methyl-4-oxo-4H-1-benzopyran
This compound was prepared according to Example 86, but using
Intermediate LXXXIX instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. It was purified
by flash chromatography on silica gel eluting with a
chloroform-methanol gradient (100:2 to 100:6) and crystallized from
95% ethanol (m.p. 166.degree.-168.degree. C.).
Example 112
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-6-methan
esulfonylamino-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride
0.032 ml of methanesulfonyl chloride in 1 ml of dimethylformamide
was added dropwise in 10 minutes to a solution of 0.21 g of
compound of Example 94 and 0.062 ml of triethylamine in 4 ml of
dimethylformamide, stirred at -20.degree. C. Stirring was continued
at the same temperature for 3.5 hours. After this period, the
reaction mixture was poured into water and the suspension was
filtered by suction, yielding 0.1 g of the title compound which was
recrystallized from 80% ethanol (m.p. 272.degree.-275.degree.
C.).
Example 113
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(4-nitr
ophenyl)-4-oxo-4H-1-benzopyran
The title compound was prepared following the procedure described
in Example 90, but starting from Intermediate XCVIII instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. After 1 hour stirring at room temperature, the reaction
mixture was poured into cold 2% aqueous sodium carbonate solution
and the precipitated solid was collected by suction. After
desiccation and crystallization from ethanol, the title compound
melted at (60) 185.degree.-187.degree. C.
Example 114
6-Diethoxyphosphonyloxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarba
moyl}-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran
The title compound was prepared following the procedure described
in Example 90, but starting from Intermediate LXIII instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid
and using 2 equivalents of diethyl cyanophosphate instead of 1.1
equivalent. Filtration from water yielded the title compound
melting at 48.degree.-80.degree. C. with decomposition.
Example 115
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-t
rifluoromethyl-4H-1-benzopyran methanesulfonate 2/3 H.sub.2 O
The title compound was obtained by the same method as described in
Example 90, but starting from Intermediate C instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. After the usual workup by extraction with ethyl acetate, the
residue was purified by column chromatography on silica gel eluting
with ethyl acetate-methanol (9:1), yielding the title compound as a
pure base, which was converted into its methanesulfonate by the
usual procedure and recrystallized from ethyl acetate (m.p.
145.degree.-148.degree. C.).
Example 116
8-{N,3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl-N-methylcarbamoyl}-3-meth
yl-4-oxo-2-phenyl-4H-1-benzopyran hydrochloride. 0.66 H.sub.2 O
This compound was prepared according to Example 12, using
Intermediate CI instead of
3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine. The crude base
was purified by flash chromatography on silica gel, eluting with
chloroform-5N ammonia in methanol (100:1) and transformed into the
hydrochloride in the usual way. The obtained title compound melted
at 195.degree.-198.degree. C., after crystallization from
acetone.
Example 117
2-Benzoyl-3-ethyl-7-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}b
enzo[b]furan
This compound was prepared according to Example 86, but using
Intermediate CIII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, and completing
the reaction at room temperature for 4 hours. It was purified by
crystallization from ethanol (m.p. 165.degree.-166.degree. C.).
Example 118
2-(4-Biphenylyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-
3-methyl-4-oxo-4H-1-benzopyran
The title compound was prepared according to Example 86, but using
Intermediate CVI instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The reaction
lasted 20 hours at room temperature. The base was purified by
crystallization from ethanol (m.p. 164.degree.-166.degree. C.).
Example 119
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
3-pyridyl)-4H-1-benzopyran
A mixture of 6.2 g of methyl 3-propionylsalicylate and 5.8 g of
nicotinoyl chloride hydrochloride in 18 ml of anhydrous pyridine
was stirred and heated at 100.degree. C. for 2 hours under
nitrogen. After that, 16 ml of triethylamine was added and heating
was continued for 1 hour at the same temperature. The reaction
mixture was cooled to room temperature, poured into 600 ml of water
and the precipitate was collected by suction and washed with water,
yielding 5.4 g of methyl
2-hydroxy-3-(2-nicotinoyl)propionylbenzoate, which was used without
purification in the next step. 3.4 g of this Intermediate was
heated at 100.degree. C. for 1.5 hours after dissolution in a
mixture containing 15 ml of acetic acid and 1 ml of 37%
hydrochloric acid. After cooling to room temperature, the mixture
was poured into 150 ml of water and extracted with ethyl acetate.
The organic phase was washed with 5% aqueous sodium hydrogen
carbonate solution, followed by water, dried on sodium sulfate and
evaporated in vacuo, yielding 1.3 g of crude methyl
3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran-8-carboxylate. 1 g of
the above ester was dissolved in 9 ml of methanol and 15 ml of
1,4-dioxane and slowly added with 1.7 ml of 10N sodium hydroxide,
maintaining the temperature between 20 and 25.degree. C. After 1
hour at 50.degree. C., the reaction mixture was poured into 150 ml
of water and extracted with ethyl acetate. The aqueous layer was
acidified with in aqueous hydrochloric acid solution. The
precipitate was collected by suction, yielding 0.6 g of
3-methyl-4-oxo-2-(3-pyridyl)-4H-1-benzopyran-8-carboxylic acid,
which was used without purification in the next step. The title
compound was prepared according to Example 86, but using the above
Intermediate instead of 4-oxo-2-phenyl-4H-1-
benzopyran-8-carboxylic acid and carrying out the reaction for 2
hours at room temperature. The base was purified by flash
chromatography on silica gel eluting with a mixture of
chloroform-methanol (98:2), followed by crystallization from
acetone, yielding 0.15 g (m.p. 134.5.degree.-137.degree. C.).
Example 120
8-{3-[4-(2-Acetoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran
1 g of compound of Example 59 and 0.32 g of 4-dimethylaminopyridine
were dissolved in 10 ml of dichloromethane and slowly added with
0.15 ml of acetyl chloride, maintaining the temperature between
8.degree. and 10.degree. C. After 2 hours at room temperature, the
reaction mixture was poured into 70 ml of water and extracted with
dichloromethane. The organic layer was washed with 5% aqueous
sodium hydrogen carbonate solution, followed by water, dried on
anhydrous sodium sulfate and evaporated in vacuo. The crude base
was purified by flash chromatography on silica gel eluting with a
mixture of ethyl acetate-methanol (9:1), followed by
crystallization from ethanol, yielding 0.74 g of the title compound
(m.p. 120.degree.-123.degree. C.).
Example 121
3-Methyl-8-{3-[4-(2-methylaminocarbonyloxyphenyl)-1-piperazinyl]-propylcarb
amoyl}-4-oxo-2-phenyl-4H-1-benzopyran
3 g of compound of Example 59 and 18 ml of methyl isocyanate were
dissolved in 30 ml of dry N,N-dimethylformamide and stirred at room
temperature for 24 hours. The mixture was diluted with water,
stirred for 2 hours, then filtered by suction. The crude base was
purified by flash chromatography on silica gel eluting with
chloroform-5N ammonia in methanol (100:3). The title compound
melted at 132.degree.-135.degree. C. after crystallization from
ethanol.
Example 122
6-Acetoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran
0.17 ml of acetyl chloride was added dropwise during 5 minutes,
under stirring at 0.degree. C., into a solution of 1 g of the
compound of Example 91 and 0.32 ml of triethylamine in 36 ml of
chloroform. After 2 hours stirring at the same temperature, the
reaction mixture was diluted with dichloromethane and water; the
organic layer was separated, washed with water, dried on sodium
sulfate and evaporated to dryness in vacuo. Crystallization of the
residue from acetonitrile yielded 0.8 g of the title compound,
melting at 148.degree.-149.degree. C.
Example 123
(R,S)-2,3-dihydro-4-hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylc
arbamoyl}-4H-1-benzopyran methanesulfonate
The title compound was prepared by the same method as described in
Example 17 but starting from compound of Example 87 instead of
compound of Example 1. The reaction mixture was diluted with water
and stirred for 15 minutes. Thereafter, it was extracted with ethyl
acetate. Usual work up gave a crude residue, which was purified by
flash chromatography on silica gel eluting with
dichloromethane-methanol (95:5). Evaporation in vacuo of the
collected fractions yielded the pure base, which was converted into
the methanesulfonate and crystallized from acetonitrile (m.p.
172.degree.-175.degree. C.).
Example 124
2-(4-Aminophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-
3-methyl-4-oxo-4H-1-benzopyran
2.22 g of compound of Example 113 and 0.56 g of Raney-Nickel in 96
ml of ethanol and 4.8 ml of acetic acid was hydrogenated in a Parr
apparatus (pH.sub.2 =1 atm) at room temperature. After 6 hours
shaking, the catalyst was filtered off and the filtrate was
alkalinized with 3N aqueous sodium hydroxide solution and diluted
with water. After standing for 2 days at 0.degree. C., the
precipitated title compound was collected by suction, washed with
water, desiccated and recrystallized firstly from ethyl acetate
then from ethanol yielding 1.5 g of the title compound (m.p.
192.degree.-194.degree. C.).
Example 125
2-(4-Acetylaminophenyl)-8-{3-[4-(2-methoxyphenyl)-1piperazinyl]propylcarbam
oyl}-3-methyl-4H-1-benzopyran
The title compound was prepared by the same method as described for
compound of Example 36, but using the compound prepared in Example
124 instead of compound of Example 33. It was purified by
crystallization from 95% ethanol (m.p. 209.degree.-211.degree.
C.).
Example 126
2-(4-Hydroxyphenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl
}-3-methyl-4H-1-benzopyran dihydrochloride monohydrate
The title compound was prepared by the method described in Example
86 but using Intermediate CVII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, and carrying out
the reaction for 14 hours at room temperature also in the presence
of hexamethylphosphoramide as co-solvent. The isolated
diethylphosphonyl ester of the title compound was hydrolyzed by
alkaline treatment followed by neutralization with diluted
hydrochloric acid. The crude base was extracted with chloroform and
the organic layer washed with water and evaporated in vacuo. The
salt was prepared by ethanolic hydrogen chloride addition to an
acetone solution of the base, evaporating to dryness and rinsing
with acetone (m.p. 193.degree.-205.degree. C.).
Example 127
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenyl-4,
N.sub.1, N.sub.4 -trioxo-4H-1-benzothiopyran monohydrate
0.8 g of compound of Example 107 and 15 ml of acetic acid were
added with 0.32 ml of 30% hydrogen peroxide and stirred at
50.degree. C. for 3 hours. Then 0.48 ml of 30% hydrogen peroxide
(3.times.0.16 ml portions every 2 hours of heating) was added to
the mixture. After cooling, the mixture was poured into 240 ml of
water, neutralized at pH 7 with 5% aqueous sodium hydrogen
carbonate solution and extracted with chloroform. The organic layer
was washed with water, dried on anhydrous sodium sulfate and
evaporated in vacuo, yielding 0.18 g of the title compound, melting
at 172.degree.-175.degree. C. after crystallization from
acetonitrile.
Example 128
7-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenylbenzo[b]fu
ran
The title compound was prepared by the method described in Example
86 but using 2-phenylbenzo[b]furan-7-carboxylic acid (prepared as
described in EP 306,226) instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, and carrying out
the reaction for 1.5 hours at room temperature. It was purified by
crystallization from carbon tetrachloride (m.p.
132.degree.-136.degree. C.).
Example 129
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl-N-methylsulfamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate
2.29 g of Intermediate VIII was added portionwise under stirring at
0.degree. C. to a solution of 1.5 g of Intermediate CI and 0.95 ml
of triethylamine in 30 ml of chloroform. After 2 additional hours
stirring at room temperature, the reaction mixture was diluted with
dichloromethane, water and 0.5N sodium hydroxide. The organic layer
was washed with water, dried on sodium sulfate and evaporated to
dryness in vacuo. The residue was purified by flash chromatography
on silica gel eluting with ethyl acetate-methanol (96:4).
Evaporation in vacuo of the collected fractions, yielded of the
pure title compound as a base. This one was converted by the usual
method into the methanesulfonate salt, which was crystallized from
ethyl acetate yielding 2.75 g, melting at 135.degree.-141.degree.
C. (dec.).
Example 130
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]-butyl-N-methylsulphamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate
The title compound was obtained by the same method described in
Example 129 but using Intermediate CVIII instead of Intermediate
CI. The title compound was crystallized from acetonitrile (m.p.
173.degree.-175.degree. C.).
Example 131
2-(4-Dimethylaminophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcar
bamoyl}-3-methyl-4-oxo-4H-1-benzopyran
The title compound was prepared by the same method as described for
compound of Example 97, but using the compound prepared in Example
124 instead of compound of Example 94. The reaction mixture was
diluted with water and 3N aqueous sodium hydroxide solution, under
vigorous stirring. The precipitated solid was filtered by suction,
washed with water, desiccated and purified by flash chromatography
on silica gel eluting with ethyl acetate - methanol (8.5:1.5).
Evaporation in vacuo of the collected fractions yielded the title
compound which melted at 146.degree.-150 (164) .degree. C after
crystallization from acetonitrile.
Example 132
3-Benzyloxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-
2-phenyl-4H-1-benzopyran
The title compound was prepared according to the method described
in Example 90, but using Intermediate CXI instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The crude title compound was recovered by suction filtration
and purified by flash chromatography on silica gel, eluting with
chloroform-methanol (95:5). Evaporation in vacuo of the collected
fractions gave the pure title compound, which was recrystallized
twice from ethanol, m.p. 159.degree.-161.degree. C.
Example 133
8-{3-[4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl
-4-oxo-2-phenyl-4H-1-benzopyran methanesulfonate 0.25 H..sub.2
O
A homogeneous mixture of 0.59 g of
1-(4-hydroxy-2-methoxyphenyl)piperazine (prepared as described in
J. C. Pascal et al, Eur. J. Med. Chem., 25, 291 (1990)) 0.89 g of
intermediate XXXVII and 0.35 g of anhydrous potassium carbonate was
heated at 180.degree. C. for 15 minutes. After cooling to room
temperature, the reaction mixture solidified and was extracted with
chloroform. After washing with water, the organic layer was dried
on sodium sulfate and evaporated to dryness in vacuo. The crude
material was purified by flash chromatography on silica gel eluting
with ethyl acetate-methanol (9:1). Evaporation in vacuo of the
collected fraction yielded 0.99 g of the pure title compound as a
base, which was converted in the usual manner into the
methanesulfonate salt. Recrystallization from acetonitrile yielded
0.85 g of the title compound, m.p. (147) 150.degree.-186.degree. C.
with decomposition.
Example 134
8-{3-[2-(8-methoxy-1,4-benzodioxanyl)methylamino]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran
A mixture of 5.52 g of 8-hydroxy-2-hydroxymethyl-1,4-benzodioxan
(prepared as described in EP 210581), 4.2g of anhydrous potassium
carbonate and 2.06 ml of methyl iodide in 75 ml of anhydrous
dimethylformamide was stirred at 45.degree. C. for 8 hours. Methyl
iodide (1 ml) was added to the mixture and stirring continued at
the same temperature. After 8 hours, 1 ml of methyl iodide and 2.1
g of potassium carbonate were further added, and the reaction
mixture was stirred at 45.degree. C. for 6 hours. Thereafter, the
mixture was cooled to room temperature, poured into water and
extracted with ethyl acetate. The organic layer was washed with 6N
aqueous sodium hydroxide solution, water, then dried on sodium
sulfate. Evaporation of the organic layer to dryness in vacuo
afforded 5.35 g of 2-hydroxymethyl-8-methoxy-1,4-benzodioxan, which
was used in the next step without further purification.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3 (.delta.)) 6.78 (1H,
t, CH of benzodioxan ring in 6) 6.55, 6.48 (2H, 2dd, CHs of
benzodioxan ring in 5 and 7) 4.20.degree.-4.35 (2H, m, CH.sub.eq in
3 and CH in 2 of benzopyran ring) 4.11 (1H, q, CH.sub.ax in 3 of
benzopyran ring) 3.80-3.95 (2H, m, CH.sub.2 O) 3.85 (3H, s,
CH.sub.3 O) 3.00 (1H, bs, OH)
5.35 g of the above Intermediate and 5.2 g of p-toluenesulfonyl
chloride in 55 ml of anhydrous pyridine was stirred at 0.degree. C.
for 3 hours. The reaction mixture was poured into water, containing
75 ml of 37% hydrochloric acid, and extracted with ethyl acetate.
The organic layer was washed with water, dried on sodium sulfate
and evaporated to dryness in vacuo. The residue was crystallized
from cyclohexane-benzene to give 5.2 g of
8-methoxy-2-p-toluenesulfonyloxymethyl-l,4-benzodioxan.
.sup.1 H-NMR Spectrum at 60 MHz (CDCl.sub.3 (.delta.)) 7.55, 7.25
(4H, 2dd, CHs of toluene ring) 6.30-6.80 (3H, m, CHs of benzopyran
ring) 4.00-4.50 (4H, m, CH.sub.2 OS, CH.sub.eq in 3 and CH in 2 of
benzopyran) 3.80 (4H, bs, CH.sub.3 O and CH.sub.eq in 3 of
benzopyran ring) 2.40 (3H, s, CH.sub.3 of tosyl group)
The title compound was prepared according to the procedure
described in Example 52, but using 1.2 molar equivalent of
Intermediate XLIII and 1 molar equivalent of the above
8-methoxy-2-(p-toluensulfonyloxymethyl)-1,4-benzodioxan instead of
2-(p-toluenesulfonyloxymethyl)-1,4-benzodioxan.
The crude was purified by flash chromatography eluting with an
ethyl acetate-methanol gradient (9:1 to 8:2). Evaporation in vacuo
of the collected fractions, yielded the title compound, m.p.
63.degree.-108.degree. C. (with decomposition).
Example 135
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenyl-4-thioxo-
4H-1-benzopyran methanesulfonate
The title compound was obtained by the same method of compound
described in Example 87, but starting from Intermediate CXIII
instead of 2,3-dihydro-4-oxo-4H-1-benzopyran-8-carboxylic acid. The
corresponding carbonyl chloride was obtained by stirring for three
hours at room temperature and 0.5 hour at reflux instead of 1.5
hour at room temperature. The crude was purified by flash
chromatography on silica gel eluting with ethyl acetate-methanol
(98:2), giving the pure title compound as a base, which was
converted in the usual manner into the methanesulfonate and
recrystallized from acetonitrile, m.p.196.degree.-198.degree.
C.
Example 136
8-{[2,2-Dimethyl-3-(4-(2-methoxyphenyl)-1-piperazinyl)propyl]carbamoyl}-3-m
ethyl-4-oxo-2-phenyl-4H-1-benzopyran
0.3 g of sodium borohydride was added at 0.degree. C. to a stirred
solution of 1.54 g of Intermediate CXIV in 17 ml of ethanol. After
1 hour stirring at the same temperature, 1N aqueous hydrochloric
acid solution was added dropwise to the mixture until pH=1.
Thereafter, the reaction mixture was made basic by adding 1N
aqueous sodium hydroxide solution and extracted with ethyl acetate.
The organic layer was washed with water, dried on sodium sulfate
and evaporated to dryness in vacuo, yielding 1.54 g of
2,2-dimethyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]propanol as an
oil. The alcohol was used in the next step without further
purification.
.sup.1 H-NMR Spectrum at 60 MHz (CDCl3 (.delta.)) 6.85 (4H, s,
aromatic CHs) 3.80 (3H, s, OCH.sub.3) 3.50 (2H, s, CH.sub.2 O)
2.50-3.20 (8H, m, CH.sub.2 of piperazine ring) 2.40 (3 H, s, OH and
CH.sub.2 N ) 0.95 (6H, s, (CH.sub.3).sub.2 C)
1.5 g of the above alcohol and 1.2 g of p-toluenesulfonyl chloride
in 12 ml of anhydrous pyridine were stirred at 0.degree. C.-room
temperature for 2.5 hours. After standing for 2 days at 0.degree.
C., the reaction mixture was poured into 0.1N aqueous sodium
hydroxide solution containing ice and extracted with ethyl acetate.
The organic layer was repeatedly washed with water, dried on sodium
sulfate and evaporated to dryness in vacuo to give 2.16 g of a
crude. The above obtained crude,
2,2-dimethyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl
p-toluenesulfonate, and 1.1 g of potassium phthalimide in 15 ml of
anhydrous dimethylformamide were stirred at 110.degree. C. for 2
hours. The cooled reaction mixture was poured into water and
extracted with ethyl acetate. Usual work up yielded 0.75 g of
1-[2,2-dimethyl-3-(1-phthalimidyl)propyl]-4-(2-methoxyphenyl)piperazine,
as a crude material which was used in the next step without further
purification. 0.2 ml of 100% hydrazine hydrate was added to a
solution of 0.75 g of the above intermediate in 10 ml of 95%
aqueous ethanol solution, which was then refluxed for 2 hours. The
reaction mixture was cooled to room temperature, diluted with in
aqueous hydrochloric acid and water, then filtered by suction. The
filtrate was made alkaline with 1N aqueous sodium hydroxide
solution and extracted with dichloromethane. The organic layer was
washed with water, dried on sodium sulfate and evaporated to
dryness in vacuo, yielding 0.45 g of
2,2-dimethyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine,
which was not further purified.
.sup.1 H-NMR spectrum at 60 MHz (CDCl3 (.delta.)) 7.00 (4H, s,
phenyl CHs) 3.90 (3H, s, OCH.sub.3) 2.50-3.20 (10H, m, piperazine
CH.sub.2 s, CH.sub.2 N) 2.30 (2H, s, CH.sub.2 NH.sub.2) 1.20-1.50
(2H, bs, NH.sub.2) 0.90 (6H, s, (CH.sub.3).sub.2 C)
A solution of 0.43 g of
3-methyl-8-chlorocarbonyl-4-oxo-2-phenyl-4H-1-benzopyran in 8 ml of
dichloromethane was added dropwise at 0.degree. C. to a stirred
solution of 0.4 g of the above intermediate and 0.2 ml of
triethylamine in 4 ml of dichloromethane. After 30 minutes at room
temperature, the reaction mixture was diluted with water and the
organic layer was separated, dried on sodium sulfate and evaporated
to dryness in vacuo. The resulting crude material was purified by
flash chromatography on silica gel eluting with a petroleum
ether-ethyl acetate gradient (5:5 to 3:7).
Evaporation in vacuo of the collected fractions yielded 0.32 g of
the title compound, m.p. 62.degree.-73.degree. C.
Example 137
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
2-phenylethyl)-4H-1-benzopyran
This compound was prepared according to Example 86, but using
Intermediate CXVI instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The crude was
purified by crystallization from ethanol, m.p.
142.degree.-146.degree. C.
Example 138
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenyl-1,1,4-tri
oxo-4H-1-benzothiopyran hydrochloride
A mixture of 0.4 g of Intermediate CXVIII and 0.29 g of
1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine in 3 ml of
dimethylformamide was stirred at room temperature for 90 minutes,
then it was poured into 100 ml of water. After extraction with
chloroform and evaporation in vacuo of the organic layer, the crude
material was purified by flash chromatography on silica gel eluting
with chloroform-methanol (100:5). The oily base was dissolved in
ethanol and an excess of 5N ethanolic hydrogen chloride was added
to the solution, followed by diethyl ether addition until the title
compound crystallized. Yield 0.2 g, m.p. 187.degree.-189.degree.
C.
Example 139
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran-N.sub.1 -oxide hydrate
A solution of 2.05 g of magnesium peroxyphthalate in 25 ml of water
was added dropwise at 15.degree.-20.degree. C. to a stirred mixture
of 3.5 g of the compound prepared in Example 11 in 60 ml of
methanol and 5 ml of chloroform. After stirring at room temperature
for 3 hours, solvents were evaporated in vacuo and the residue was
treated with 50 ml of water, made alkaline with aqueous 5% sodium
hydrogen carbonate addition, then extracted with chloroform. The
separated organic layer was dried over sodium sulfate, evaporated
to dryness in vacuo, and the resulting residue was purified by
flash chromatography on silica gel eluting with a
dichloromethane-5N methanolic ammonia gradient (100:5 to 100:15).
The purification was again repeated by flash chromatography on
silica gel eluting with n-butyl alcohol saturated with water and
acetic acid. The fractions containing the title compound were
pooled, diluted with water and made alkaline (pH>10) by addition
of 20% aqueous sodium carbonate solution. The mixture was extracted
with chloroform, the separated organic layer was washed with water,
dried over anhydrous sodium sulfate and the solvent was evaporated
to dryness. 0.37 g of the title compound was obtained after
crystallization from ethanol, m.p. 165.degree.-167.degree. C.
Example 140
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-p
henyl-4H-1-benzopyran N.sub.1,N.sub.4 -dioxide 0.25 hydrate
The compound was isolated during the purification of the crude of
Example 139. The last fractions, collected from purification by
flash chromatography on silica gel eluting with a dichloromethane -
5N methanolic ammonia gradient (100:5 to 100:15), were evaporated
to dryness and the residue was crystallized from acetonitrile,
yielding 0.5 g of the title compound, m.p. 170.degree.-172.degree.
C.
Example 141
8-{3-[4-(5-Fluoro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran
This compound was prepared by the method described in Example 133,
but using 1-(5-fluoro-2-methoxyphenyl)piperazine (prepared as
described in GB 2,161,807) instead of
1-(4-hydroxy-2-methoxyphenyl)piperazine. The reaction lasted 30
minutes and the crude material was purified by flash chromatography
on silica gel eluting with chloroform - 2N triethylamine in
methanol (100:1). The title compound melted at
146.degree.-148.degree. C., after crystallization from
acetonitrile.
Example 142
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-phenyl=4(1H)-qui
nolone
A solution of 0.78 g of N,N'-dicyclohexylcarbodiimide in 8 ml of
anhydrous dimethylformamide was added dropwise over 5 minutes at
4.degree. C. to a stirred mixture of 1 g of
2-phenyl-4(1H)-quinolone-8-carboxylic acid (prepared as described
in W. A. Denny et al., J. Med. Chem., 32, 396 (1989)) and 0.43 g of
N-hydroxysuccinimide in 12 ml of anhydrous dimethylformamide under
nitrogen atmosphere. After 1 hour at room temperature, the
insoluble N,N'-dicyclohexylurea was filtered off by suction and a
solution of 1-(3-aminopropyl)-4-(2-methoxyphenyl)piperazine in 6 ml
of anhydrous dimethylformamide was added dropwise, over 5 minutes,
to the reaction solution. After 4 hours at room temperature, the
mixture was poured into water, extracted with ethyl acetate and the
crude obtained after evaporation of the organic layer was purified
by flash chromatography on silica gel eluting with
chloroform-methanol (100:5). 0.8 g of the title compound was
obtained after crystallization from acetone, m.p.
135.degree.-140.degree. C.
Example 143
2-(4-Cyanophenyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-
3-methyl-4-oxo-4H-1-benzopyran
The title compound was prepared by the method described in Example
142, but using Intermediate CXX instead of
2-phenyl-4(1H)-quinolone-8-carboxylic acid. The crude material was
purified by flash chromatography on silica gel eluting with
chloroform-methanol (100:1). The title compound had a melting point
of 167.degree.-170.degree. C., after crystallization from
ethanol.
Example 144
6-Cyano-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}3-methyl-4-
oxo-2-phenyl-4H-1-benzopyran
The title compound was prepared by the method described in Example
142, but using Intermediate CXXII instead of
2-phenyl-4(1H)-quinolone-8-carboxylic acid. The crude material was
purified by flash chromatography on silica gel eluting with
dichloromethane-methanol (100:2). The title compound was obtained
after crystallization from acetonitrile, m.p.
165.5.degree.-167.degree. C.
Example 145
8-{3-[4-(4-Fluoro-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-
4-oxo-2-phenyl-4H-1-benzopyran
The title compound was prepared by the method described in Example
133, but using 1-(4-fluoro-2-methoxyphenyl)piperazine (prepared as
described in GB 2,161,807) instead of
1-(4-hydroxy-2-methoxy-phenyl)piperazine. The crude material was
purified by flash chromatography on silica gel eluting with
chloroform-2N methanolic triethylamine (100:1). The title compound
was obtained after crystallization from acetonitrile, m.p.
169.degree.-171.degree. C.
Example 146
8-{3-[4-(3-Methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran
The title compound was prepared by the method described in Example
133, but using 1-(3-methoxyphenyl)piperazine instead of
1-(4-hydroxy-2-methoxyphenyl)piperazine. The crude material was
purified by flash chromatography on silica gel eluting with
dichloromethane-methanol gradient (100:2 to 100:3). The title
compound was obtained after crystallization from acetonitrile, m.p.
130.degree.-132.5.degree. C.
Example 147
8-{3-[4-(4-Methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran
The title compound was prepared by the method described in Example
133, but using 1-(4-methoxyphenyl)piperazine instead of
1-(4-hydroxy-2-methoxyphenyl)piperazine. The crude material was
purified by flash chromatography on silica gel eluting with
dichloromethane-methanol (100:2). The title compound was obtained
after crystallization from acetonitrile, m.p.
182.degree.-184.degree. C.
Example 148
3-Methoxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-
phenyl-4H-1-benzopyran
The title compound was prepared following the procedure of Example
90, but using Intermediate CXXIV instead of
6-methoxy-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The
crude material was crystallized from ethanol, yielding the title
compound, m.p. 145.degree.-146.degree. C.
Example 149
3-Hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-
phenyl-4H-1-benzopyran
The title compound was prepared according to Example 142, using
Intermediate CXXXIII instead of
2-phenyl-4(1H)-quinolone-8-carboxylic acid. The crude product was
recovered by filtration (in vacuo) was purified by flash
chromatography on silica gel using dichloromethane/methanol (95:5)
as the eluent. After evaporation to dryness, (in vacuo) of the
solvent from the combined fractions, the residue was washed with
hot acetone. The title compound was crystallized from acetonitrile,
m.p. 196.degree.-199.degree. C.
Example 150
2-Cyclohexyl-3,4-dihydro-8-{3-[4-(2-methoxyphenyl)1-piperazinyl]propylcarba
moyl}-2H-1-benzopyran
The title compound was obtained following the method described in
Example 90 starting from 1.59 g of Intermediate CXXXVI instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The crude product was purified by flash chromatography
eluting with an ethyl acetate/methanol (98:2) mixture. Evaporation
of the solvent from (in vacuo) the collected fractions, was
followed by crystallization from cyclohexane, to provide 1.5 g of
the title compound, m.p. 79.degree.-83.degree. C.
Example 151
2-Benzyl-3-ethyl-7-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}be
nzo[b]furan
This compound was prepared by the method described in Example 142,
using Intermediate CXXVI instead of
2-phenyl-4-(1H)-quinolone-8-carboxylic acid. Crystallization from
acetone/water (9:1) provided the title compound, m.p.
110.degree.-112.degree. C.
Example 152
8-{3-[4-(2-Isopropoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-
2-phenyl-4H-1-benzopyran dihydrochloride
This compound was prepared by the method described in Example 133,
using 1-(2-isopropoxyphenyl)piperazine (prepared as described in
Martin G. E. et al., J. Med. Chem., 32, 1052 (1989)) instead of
1-(4-hydroxy-2-methoxyphenyl)piperazine. The reaction was conducted
for 30 minutes. The crude product was purified by flash
chromatography on silica gel eluting with dichloromethane/methanol
(100:2). The pure title compound, obtained as a base, was converted
in the usual manner into the dihydrochloride salt. The salt was
crystallized from isopropanol/ethyl acetate (45:55), m p.
208.degree.-212.degree. C.
Example 153
8-{[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl]methyl}-3-methyl-4
-oxo-2-phenyl-4H-1-benzopyran
This compound was prepared by the method described in Example 86,
using Intermediate XLVII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The title
compound was purified by crystallization from ethyl acetate, m.p.
137.degree.-140.degree. C.
Example 154
8-{3-[4-[5-(1,4-Benzodioxanyl)]-1-piperazinyl]propylcarbamoyl}-3-methyl-4-o
xo-2-phenyl-4H-1-benzopyran
The title compound was obtained following the method described in
Example 133, using 1-[5-(1,4-benzodioxanyl)]piperazine (prepared as
described in EP 138,280) instead of
1-(4-hydroxy-2-methoxyphenyl)piperazine. The crude product was
purified by flash chromatography (elution mixture
chloroform/methanol 97:3). Crystallization from ethyl
acetate/2-propanol (3:1) provided the title compound melting at
111.degree.-117.degree. C.
Example 155
3-Ethoxymethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-o
xo-2-phenyl-4H-1-benzopyran
This compound was prepared according to Example 142, using
Intermediate CXLI instead of 2-phenyl-4(1H)-quinolone-8-carboxylic
acid. The reaction was carried out for 3 hours. The crude product
was purified by flash chromatography on silica gel eluting with
dichloromethane/acetonitrile (100:2). Crystallization from
acetonitrile provided the title compound, m.p.
129.degree.-133.degree. C.
Example 156
8-{[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylamino]methyl}-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran trihydrochloride. 2.5 H.sub.2 O
To a mixture of 0.53 g of
8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, 0.55 g of
3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine, 70 ml of
1,2-dichloroethane and 0.11 ml of acetic acid was added 0.64 g of
sodium triacetoxyborohydride. The mixture was stirred at room
temperature for 4.5 hours. The reaction mixture was poured into 100
ml of water and acidified with 37% hydrochloric acid. This was
followed addition of cold 6N aqueous sodium hydroxide to make the
solution alkaline. The mixture was extracted with ethyl acetate.
The organic layer was washed with water and dried over anhydrous
sodium sulfate. After evaporation of the solvent, (in vacuo) the
residue was purified by flash chromatography on silica gel eluting
with chloroform/methanol (100:5). The fractions containing the pure
base were combined and the solvent was evaporated to dryness. The
title compound, obtained as a base, was converted in the usual
manner into the trihydrochloride salt, and crystallized from
ethanol, m.p. 170.degree.-176.degree. C. (dec.).
Example 157
7-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-2-(4-nitrophenyl)i
ndole
A mixture of 2.2 g of methyl 2-(4-nitrophenyl)indol-7-carboxylate
(prepared as described in Filacchioni G. et al., Il Farmaco Ed.
Sci., 37, 353-365 (1982)), 1.4 g of potassium hydroxide, 20 ml of
ethanol and 20 ml of water was stirred at reflux temperature for 1
hour. After cooling to room temperature, the mixture was poured
into water and extracted with ethyl acetate. The aqueous layer was
separated, acidified by addition 37% hydrochloric acid. The
2-(4-nitrophenyl)indole-7-carboxylic acid was collected by suction
filtration and washed with water. The yield was 1.59 g.
The title compound was prepared by the method described in Example
142, using the indolecarboxylic acid prepared above instead of
2-phenyl-4(1H)-quinolone-8-carboxylic acid. The crude product was
purified by flash chromatography on silica gel eluting with
chloroform/methanol (98:2). Crystallization from ethyl acetate
provided the title compound, m.p. 188.degree.-191.degree. C.
Example 158
8-{3-[4-(5
-Hydroxy-2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran methanesulfonate. 0.75 H.sub.2 O.
A solution of 1.48 g of intermediate CXXXIV and 1.67 g of potassium
carbonate in 10 ml of water was stirred at 100.degree. C. in an
open vessel until complete evaporation of the water was obtained.
The residue was mixed with 1.42 g of Intermediate XXXVII. The
mixture was warmed to 180.degree. C. for 15 min. After cooling to
room temperature, the vitreous mass was rinsed with
dichloromethane, the inorganic materials filtered off and the
solvent evaporated (in vacuo). The residue was purified by flash
chromatography on silica gel eluting with an ethyl acetate/methanol
mixture (95:5). This provided 0.69 g of the title compound as a
base. The base was converted in the usual manner into its
methanesulfonate, m.p. 207.degree.-219.degree. C.
(acetonitrile).
Example 159
3-Ethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-ph
enyl-4H-1-benzopyran
This compound was prepared according to Example 86, using
3-ethyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid (prepared
as described in Da Re et al., Chem. Ber. 99, 1962-1965 (1966))
instead of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid.
Crystallization from ethanol provided the title compound, m.p.
133.degree.-136.degree. C.
Example 160
8-{3-[4-(2-Methoxyphenoxy)-1-piperidinyl]propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran
This compound was prepared by the method described in Example 133,
using 4-(2-methoxyphenoxy)piperidine (prepared as described in
Baswell R. F. Jr. et al., J. Med. Chem. 17, 1000.degree.-1008
(1974)) instead of 1-(4-hydroxy-2-methoxyphenyl)piperazine. The
reaction was carried out for 30 minutes. The crude product was
purified by flash chromatography on silica gel eluting with
gradient of chloroform/5N methanolic ammonia (100:2 to 100:3).
Crystallization from 95% ethanol provided the title compound, m.p.
154.degree.-156.degree. C.
Example 161
8-{3-[4-(2,3-Dihydrobenzo[b]furan-7-yl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-2-phenyl-4H-1-benzopyran - 0.75 H.sub.2 O
This compound was prepared according to Example 133, using
1-(2,3-dihydrobenzo[b]furan-7-yl)piperazine (prepared in the same
way as 1-[5-(1,4-benzodioxanyl)]piperazine, which is described in
EP 138,280) instead of 1-(4-hydroxy-2-methoxy-phenyl)piperazine
(reaction time; 30 minutes). The crude product was purified by
flash chromatography on silica gel eluting with dichloromethane/5N
methanolic ammonia (100:2). The pure title compound was stirred
with a 1:1 mixture of water and diethyl ether and heated to
35.degree.-45.degree. C. until diethyl ether was distilled off. The
product was collected by filtration, m.p. 94.degree.-95.degree.
C.
Example 162
2-(2-Biphenylyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3
-methyl-4-oxo-4H-1-benzopyran dihydrochloride. 1.25 H.sub.2 O
This compound was prepared by the method described in Example 86,
using Intermediate CXLIV instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The crude product
was purified by flash chromatography on silica gel eluting with
chloroform-5N methanolic ammonia (100:5). The pure base obtained
was transformed, in the usual manner, into the dihydrochloride.
Crystallization from ethanol/diethyl ether provided the title
compound, m.p. 188.degree.-194.degree. C.
Example 163
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(1-naph
thyl)-4-oxo-4H-1-benzopyran
This compound was prepared by the method described in Example 86,
using Intermediate CXLIII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The crude product
was purified by flash chromatography on silica gel eluting with
chloroform/5N methanolic ammonia (100:3). Crystallization from
isopropanol provided the title compound, m.p.
134.degree.-138.degree. C.
Example 164
3-Benzyloxymethyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-
2-phenyl-4H-1-benzopyran dihydrochloride
This compound was prepared according to Example 84, using
Intermediate CXLII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The title
compound, as the base, was dissolved in boiling ethanol and
acidified with a solution of 3N ethanolic hydrogen chloride. The
solid was collected by suction filtration and crystallized from
ethanol m.p. 187.degree.-192.degree. C.
Example 165
3-Methyl-8-{3-[4-[2-[(4-morpholinylmethyl)benzoyloxy]phenyl]-1-piperazinyl]
propylcarbamoyl}-4-oxo-2-phenyl-4H-1-benzopyran
A mixture of 1.74 g of
8-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-
phenyl-4H-1-benzopyran, prepared as described in Example 59, 2 ml
of triethylamine and 70 ml of dichloromethane, was stirred and
maintained at 0.degree.-5.degree. C. 4-(4-Morpholinylmethyl)benzoyl
chloride, 1.22 g, (prepared as described in U.S. Pat. No.
4,623,486) was added, in portions, to the mixture. After 1 hour
with the temperature maintained at 0.degree.-5.degree. C., the
reaction was allowed to stand for 7 days at room temperature. The
reaction mixture was extracted with water. The organic layer was
dried over anhydrous sodium sulfate and evaporated to dryness (in
vacuo). Crystallization from 96% ethanol provided 2 g of the title
compound, m.p. 106.degree.-108.degree. C.
Example 166
8-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethoxycarbonylamino}-3-methyl-4-oxo
-2-phenyl-4H-1-benzopyran methanesulfonate
A mixture of 2.8 g of
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid, 2.2 ml
of diphenylphosphorylazide, 1.4 ml of triethylamine and 2.6 g of
2-[4-(2-methoxyphenyl)-1-piperazinyl]ethanol in 30 ml of dioxane
was stirred at reflux for 6 hours. The reaction was cooled to room
temperature and filtered by suction. The filtrate was diluted with
water (150 ml) and extracted with ethyl acetate. The organic layer
was washed with water, dried on sodium sulfate and evaporated to
dryness (in vacuo). The residue was purified by flash
chromatography, eluting with an ethyl acetate/petroleum ether
mixture (85:15). The pure title compound, yield 2 g, was converted
into its methanesulfonate by the usual procedure, m.p.
177.degree.-181.degree. C., (ethyl acetate).
Example 167
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl]-3-methyl-2-(3-nitr
ophenyl)-4-oxo-4H-1-benzopyran
A mixture of 5 g of Intermediate CXXX, 1.94 g of potassium
tert-butoxide and 50 ml of anhydrous pyridine was stirred at
100.degree. C. for 3 hours under nitrogen. After cooling to room
temperature, the solvent was evaporated (in vacuo). The residue was
diluted with water, acidified with dilute hydrochloric acid and
extracted with ethyl acetate. The organic layer was washed with
water, dried over anhydrous sodium sulfate and evaporated to
dryness (in vacuo). The crude methyl
3-methyl-2-(3-nitrophenyl)-4-oxo-4H-1-benzopyran-8-carboxylate was
crystallized from acetone. The yield was 0.69 g.
A mixture of the intermediate prepared above, 10 ml of 1,4-dioxane,
13 ml of methanol and 0.088 g of sodium hydroxide was stirred at
50.degree. C. for 2 hours. After cooling to room temperature, the
mixture was poured into water, acidified with 3N hydrochloric acid
and concentrated (in vacuo). The solid was separated by filtration
to provide 0.54 g of
3-methyl-2-(3-nitrophenyl)-4-oxo-4H-1-benzopyran-8-carboxylic
acid.
The title compound was prepared according to Example 86, starting
from the acid prepared above instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The crude product
was purified by flash chromatography on silica gel eluting with
chloroform/methanol (100:5). Crystallization from ethanol provided
the title compound m.p. 135.degree.-137.degree. C.
Example 168
8-{3-[4-(2-Methoxyphenyl)-1-(1,4-diazepinyl)]propylcarbamoyl}-3-methyl-4-ox
o-2-phenyl-4H-1-benzopyran
The title compound was prepared according to the procedure reported
in Example 133 using 1-(2-methoxyphenyl)-1,4-diazepine (prepared as
described in W. ten Hoeve et al, J.O.C. 58, 5101-5106 (1993))
instead of 1-(4-hydroxy-2-methoxyphenyl)piperazine. The residue was
purified by flash chromatography (elution mixture chloroform/4.8N
methanolic ammonia; 96:4). This provided the pure title compound as
a base, m.p. 123.degree.-128.degree. C. (ethyl acetate).
Example 169
2-Cyclohexyl-3,4-dihydro-4-hydroxy-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]
-propylcarbamoyl}-2H-1-benzopyran and
Example 170
3,4-Dihydro-4-hydroxy-8-{3-[4-(2-methoxyphenyl)1-piperazinyl]propylcarbamoy
l}-2-phenyl-2H-1-benzopyran hydrochloride
A solution of 7 g of
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-4-oxo-2-phenyl-4H
-1-benzopyran, prepared in Example 86, in 350 ml of methanol was
hydrogenated in a Parr apparatus in the presence of 2.3 g of 70%
platinum dioxide at an hydrogen pressure of 40 psi. After 4 hours
shaking and resting overnight, the catalyst was filtered off and
the solvent evaporated (in vacuo). The oily residue was purified by
flash chromatography by eluting with an ethyl acetate/methanol
gradient of 99:1 up to 90:1. The compound of Example 169 was eluted
first (A fractions) followed by the compound of Example 170 (B
fractions).
Evaporation (in vacuo) of the solvent from the A fractions and
crystallization of the crude product from ethyl acetate provided
1.07 g of compound of Example 169. M.p. 128.degree.-132.degree.
C.
The residue obtained from evaporation to dryness (in vacuo) of the
B fractions was purified again by flash chromatography
(eluant:ethyl acetate/methanol 98:2). The pure compound of Example
170 obtained as a base was dissolved in ethyl acetate and 1
equivalent of 0.92M ethanolic hydrogen chloride was added. The
corresponding hydrochloride crystallized and was recovered by
suction filtration. Recrystallization from 2-propanol provided 0.35
g of the compound of Example 170, m.p. 220.degree.-222.degree. C.
The product contained 0.5 molar equivalents of 2-propanol.
Example 171
2-(1-Adamantyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-
methyl-4-oxo-4H-1-benzopyran
The title compound was prepared according to the method described
in Example 90, starting from Intermediate CXXXVIII instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The crude product was purified by flash chromatography
eluting with an ethyl acetate/methanol mixture (9:1).
Recrystallization from ethyl acetate/diisopropyl ether (1:2)
provided the title compound, m.p. 141.degree.-143.degree. C.
Example 172
8-{5-[4-(2-Methoxyphenyl)-1-piperazinyl]pentylsulfonyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran
The title compound was obtained following the procedure of Example
38, starting from Intermediate CXL instead of intermediate XLIV and
stirring at 50.degree. C. for 4 hours. The crude residue was
crystallized from 95% ethanol, m.p. 120.degree.-123.degree. C.
Example 173
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-(
3,4,5-triiodophenyl)-4H-1-benzopyran
A mixture of 3.74 g of
2-hydroxy-N,3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl-3-propionylbenzami
de dihydrochloride, Intermediate CLXVIII, 35 ml of anhydrous
pyridine and 7 g of 3,4,5-triiodobenzoyl chloride (prepared as
described by Klemme C. L. et al, J. Org. Chem. 5, 508 (1940)) was
stirred at reflux temperature for 13 hours. After cooling to room
temperature, 6.8 g of 1,8-diazabicyclo[5.4.0]undec-7-ene was added
to the mixture. Stirring was continued for 7 hours. The solvent was
evaporated (in vacuo) and the residue rinsed with water, acidified
to about pH 6 with 3N hydrochloric acid and extracted with
chloroform. The organic layer was separated, washed with water,
dried over anhydrous sodium sulfate and evaporated to dryness (in
vacuo). The crude product was purified by flash chromatography on
silica gel eluting with dichloromethane/isopropanol (95:5). The
title compound, yield, 1.16 g, was characterized by NMR
spectrum.
.sup.1 H-NMR spectrum at 200 MHz (CDCl .sub.3, (.delta.)) 1.82 (q,
2H) NCH.sub.2 CH.sub.2 CH.sub.2 N 2.15 (s, 3H) CH.sub.3 in 3,
benzopyran ring 2.45-2.60 (m, 6H) NHCH.sub.2 CH.sub.2 CH.sub.2 N;
piperazine ring, CH.sub.2 s in 2,6 2.75-2.90 (m, 4H) piperazine
ring, CH.sub.2 s in 3,5 3.68 (q, 2H) NHCH.sub.2 CH.sub.2 CH.sub.2 N
3.84 (s, 3H) OCH.sub.3 6.70 (dd, 1H) methoxyphenyl ring, CH in 3
6.75-7.05 (m, 3H) methoxyphenyl ring, CHs in 4,5,6 7.48 (dd, 1H)
benzopyran ring, CH in 6 7.80-7.90 (bs, 1H) CONH 8.16 (s, 2H)
phenyl ring, CHs in 2',6' 8.25-8.40 (m, 2H) benzopyran ring, CHs in
5,7
Example 174
2-Cyclopropyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-4H-1-benzopyran
This compound was prepared by the method described in Example 173,
using cyclopropanecarbonyl chloride instead of 3,4,5-triiodobenzoyl
chloride. After addition of 1,8-diazabicyclo[5.4.0]undec-7-ene, the
reaction mixture was stirred at reflux temperature for 2 hours. The
title compound was isolated in amorphous form melting at
139.degree.-141.degree. C.
Elemental analysis for C.sub.28 H.sub.33 N.sub.3 O.sub.4 : Calc. %:
C, 70.71; H, 6.99; N, 8.83. Found %: C, 70.36; H, 6.99; N,
8.69.
Example 175
8-{5-[4-(2-Methoxyphenyl)-1-piperazinyl]pentyl}-3-methyl-4-oxo-2-phenyl-4H-
1-benzopyran methanesulfonate
The title compound was prepared as described in the third step of
Example 53, starting from Intermediate CXLVII instead of
8-(4-oxobutyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and using
acetic acid instead of hydrochloric acid. The product was extracted
with ethyl acetate. After removal of the solvent the crude product
was purified by flash chromatography eluting with ethyl
acetate/petroleum ether (8:2). The pure base was dissolved in ethyl
acetate, and converted by the usual procedure into its
methanesulfonate. The product was filtered and dried, to provide
the title compound, m.p. 173.degree.-178.degree. C.
Example 176
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(4-meth
ylcyclohexyl)-4-oxo-4H-1-benzopyran
The title compound was synthesized following the procedure
described for Example 90, using Intermediate CXLIX instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The reaction mixture was poured into water and the
precipitated solid was filtered off. The product was recrystallized
from ethyl acetate, m.p. 166.degree.-167.5 C.
Example 177
2-Cyclopentyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-me
thyl-4-oxo-4H-1-benzopyran
This compound was prepared by the method described in Example 86,
using Intermediate CLII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The crude product
was purified by flash chromatography on silica gel eluting with
chloroform/methanol (98:2). Crystallization from acetonitrile
provided the title compound, m.p. 135.degree.-137.degree. C.
Example 178
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(1-phen
ylcyclopentyl)-4-oxo-4H-1-benzopyran
This compound was prepared by the method described in Example 86,
using Intermediate CLV instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. Crystallization
from ethanol provided the title compound, m.p.
171.degree.-172.degree. C.
Example 179
8-{3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-2-(1-meth
ylcyclohexyl)-4-oxo-4H-1-benzopyran
This compound was prepared by the method described in Example 86,
using Intermediate CLVI instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. Crystallization
from acetonitrile provided the title compound, m.p.
120.degree.-124.degree. C.
Examples 180 and 181
2-(Bicyclo[2.2.1]hept-5-en-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]pr
opylcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran
Example 180 (exo isomer dihydrochloride)
Example 181 (endo isomer hydrochloride. 0.75 H.sub.2 O)
These compounds were prepared by the method described in Example
86, using Intermediate CLVIII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The base was
dissolved in ethanol and 2 equivalents of ethanolic hydrogen
chloride were added to provide the title compound dihydrochloride
as the exo isomer, m.p. 184.degree.-188.degree. C. after
crystallization from ethanol and drying (in vacuo).
The amorphous material obtained by evaporation to dryness of the
crystallization liquor was crystallized from acetone to provide
2-(bicyclo[2.2.1]hept-5-en-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]p
ropylcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran hydrochloride. 0.5
H.sub.2 O as 1:1 a mixture (endo-exo) of isomers (NMR), m.p.
171.degree.-175.degree. C. The base obtained from the above
endo-exo mixture was purified by repeated flash chromatography on
silica gel eluting with chloroform/3N methanolic ammonia (100:2).
The fractions containing the first eluted substance were combined
and the solvent were evaporated (in vacuo) to provide the crude
base. The base was dissolved in chloroform and 1 equivalent of
hydrogen chloride in isopropanol was added. After crystallization
from acetonitrile the hydrochloride of the endo isomer was
obtained, m.p. 178.degree.-181.degree. C.
Example 182
2-(Bicyclo[2.2.1]heptan-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propy
lcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran hydrochloride
hemi-hydrate
The 1:1 mixture of endo-exo isomers 0.56 g from Examples 180 and
181, were combined with 30 ml of methanol and 0.15 g of 5%
palladium on charcoal and reduced with hydrogen in a Parr apparatus
at room temperature and 45 psi until the theoretical amount of
hydrogen was absorbed. The catalyst was separated by filtration and
the solvent was evaporated to dryness. The crude product was
purified by crystallization from acetonitrile to provide 0.32 g of
the title compound as a 1:1 mixture of endo-exo isomers, m.p.
172.degree.-178.degree. C.
Example 183
2-Cyclohepthyl-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl}-3-
methyl-4-oxo-4H-1-benzopyran
The title compound was prepared by the method described in Example
86, using Intermediate CLIX instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. After quenching
with water, the precipitate was extracted with chloroform. The
organic layer was separated, dried over anhydrous sodium sulfate,
and evaporated to dryness (in vacuo). The crude product was
crystallized from acetonitrile to provide the title compound, m.p.
122.degree.-128.degree. C.
Example 184
8-[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propylcarbamoyl}-1-methyl-2-phenyl-
1,2,3,4-tetrahydroquinoline
This compound was prepared by the method described in Example 86,
using Intermediate CLXIII instead of
4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid. The title
compound was obtained as a thick oil and characterized by NMR
spectrum.
.sup.1 H-NMR Spectrum at 200 MHz (CDCl3, (.delta.) 1.75 (m, 2H)
CONHCH.sub.2 CH.sub.2 CH.sub.2 1.95-2.30 (m, 2H) CH.sub.2 in 3,
tetrahydroquinoline ring 2.50 (m, 2H) CONHCH.sub.2 CH.sub.2
CH.sub.2 2.55-2.70 (m, 4H) CH.sub.2 s in 2 and 6, piperazine ring
2.72 (s, 3H) NCH.sub.3 2.75-2.90 (m, 2H) CH.sub.2 in 4,
tetrahydroquinoline ring 2.95-3.10 (m, 4H) CH.sub.2 s in 3 and 5,
piperazine ring 3.35-3.55 (m, 2H) CONHCH.sub.2 CH.sub.2 CH.sub.2
3.85 (s, 3H) OCH.sub.3 4.15 (dd, 1H) CH in 2, tetrahydroquinoline
ring 6.80-6.95 (m, 4H) CHs of methoxyphenyl ring 7.05 (dd, 1H) CH
in 6, tetrahydroquinoline ring 7.25-7.40 (m, 6H) phenyl CHs in 2,
tetrahydroquinoline and CH in 5, tetrahydroquinoline ring 7.65 (dd,
1H) CH in 7, tetrahydroquinoline ring 8.10 (m, 1H) CONH
Example 185
(Trans)-2-(4-methoxycyclohexyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]pro
pylcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran
The title compound was synthesized according to the procedure
described in example 90 using 0.73 g of Intermediate CLXVI instead
of 6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. After the usual work up, crystallization from ethyl acetate
provided 1.2 g of the title compound, m.p.
167.5.degree.-169.5.degree. C.
Example 186
(Cis)-2-(4-methoxycyclohexyl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propy
lcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran
The title compound was synthesized according to the procedure
described in Example 90, using 0.65 g of Intermediate CLXVII
instead of
6-methoxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic
acid. The usual work up provided 1 g of the title compound as
solid, m.p. 121.degree.-125.degree. C.
.sup.1 H-NMR spectrum at 200 MHz (CDCl.sub.3 (.delta.)): 8.38-8.48
(m, 2H) benzopyran, CHs in 5 and 7 7.65-7.77 (bt, 1H) NHCO 7.42
(dd, 1H) benzopyran, CH in 6 6.53-7.03 (m, 4H) phenyl ring CHs 3.84
(s, 3H) aryl OCH.sub.3 3.51-3.75 (m, 2H) CH.sub.2 NHCO 3.52-3.61
(m, 1H) CHOCH.sub.3, eq. 3.37 (s, 3H) CHOCH.sub.3, ax. 2.90-3.16
(m, 5H) cyclohexyl CH in 1 and piperazine CH.sub.2 2.50-2.72 (m,
6H) CH.sub.2 N and piperazine CH.sub.2 1.97-2.25 (m, 9H) cyclohexyl
CHs, CH.sub.3 C, CH.sub.2 -CH.sub.2, -NHCO 1.40-1.80 (m, 4H)
cyclohexyl CHs
Example 187
8-{3-[4-(7-Benzofuranyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran
The title compound was synthesized following the method described
in Example 133, using 1-(7-benzofuranyl)piperazine (prepared as
described in I. van Wijngaarden et al, J. Med. Chem. 31, 1934-1940
(1988)). The crude product was purified by flash chromatography
(eluent chloroform/methanol 97:3). Evaporation (in vacuo) to
dryness of the combined fractions provided the title compound, m.p.
120.degree.-121.degree. C. (ethyl acetate/diisopropyl ether
1:1).
.sup.1 H-NMR Spectrum at 200 MHz (CDCl.sub.3): 8.32-8.42 (m, 2H)
benzopyran, CHs in 5 and 7 7.64-7.78 (m, 3H) NHCO and phenyl CHs in
2,6 7.50-7.62 (m, 4H) phenyl, CHs in 3,4,5 and benzofuran, CH in 2
7.47 (dd, 1H) benzopyran, CH in 6 7.10-7.25 (m, 2H) benzofuran, CHs
in 4 and 5 6.75 (d, 1H) benzofuran CH in 3 6.63 (dd, 1H) benzofuran
CH in 6 3.50-3.63 (m, 2H) CH.sub.2 NHCO 3.13-3.28 (m, 4H)
piperazine CH.sub.2 s 2.51-2.63 (m, 4H) piperazine CH.sub.2 s 2.46
(t, 2H) CH.sub.2 N 2.19 (s, 3H) CH.sub.3 C 1.68-1.88 (m, 2H)
C-CH.sub.2 C
Example 188
2-(Bicyclo[2.2.1]heptan-2-yl)-8-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propy
lcarbamoyl}-3-methyl-4-oxo-4H-1-benzopyran hydrochloride hydrate
(exo isomer).
A 97:3 mixture of exo:endo isomers, 0.68 g, from Examples 180 and
181, were combined with 40 mL of methanol and 0.2 g of 5% palladium
on charcoal and reduced with hydrogen in a Parr apparatus at room
temperature and 45 psi until the theoretical amount of hydrogen was
absorbed. The catalyst was separated by filtration and the solvent
was removed (in vacuo). The crude product was solidified by
stirring with a minimum amount of acetone. Crystallization from
acetonitrile provided the title compound, 0.35 g, as a 98:2 mixture
of exo:endo isomers, m.p. 177.degree.-181.degree. C.
Example 189
8-{3-[4-(2-Chlorophenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran.
The title compound was prepared according to Example 133, using
1-(2-chlorophenyl)piperazine instead of
1-(4-hydroxy-2-methoxyphenyl)piperazine. The reaction was conducted
for 30 minutes. The crude product was purified by flash
chromatography on silica gel eluting with ethyl acetate/methanol
(gradient 100:0 to 100:2). Crystallization from ethanol provided
the title compound, m.p. 149.degree.-151.degree. C.
Example 190
8-{3-[4-(4-Chlorophenyl)-1-piperazinyl]propylcarbamoyl}-3-methyl-4-oxo-2-ph
enyl-4H-1-benzopyran.
The title compound was prepared according to Example 133, using
1-(4-chlorophenyl)piperazine instead of
1-(4-hydroxy-2-methoxyphenyl)piperazine. The reaction was conducted
for 30 minutes. The crude product was purified by flash
chromatography on silica gel eluting with ethyl acetate/methanol
(gradient 100:0 to 100:20). Crystallization from acetonitrile
provided the title compound m.p. 200.degree.-204.degree. C.
PHARMACOLOGICAL DATA
Methodology
Male Sprague Dawley rats [Crl: CD'BR] of 175-300 g b.w., female
Albino Swiss mice [Crl: CD-1 (ICR) BR] 20-30 g b.w., male Beagle
dogs (8-12 kg b.w.) were obtained from Charles River, Italy and
Nossan (Correzzana, Milan, Italy), respectively. Male white
New-Zealand rabbits, weighing 3-3.5 kg, aging 6-8 months, were
obtained from Conelli Allevamenti (Novara-Italy). Animals were
housed with free access to food and water and maintained on forced
light-dark cycle at 22.degree.-24.degree. C. until the day of
experiments.
Acute toxicity
The acute toxicity of synthesized compounds was evaluated in female
albino Swiss mice after intraperitoneal and oral administration.
Four logarithmic scaled doses of the compounds were dissolved or
suspended in 0.5% Methocel and administered in a volume of 10 ml/kg
to groups of 4 mice/dose. Mortality was recorded 7 days after the
administration. Data analysis: the LD.sub.50 values and their
fiducial limits were calculated according to the method of Weil
(Biometrics, 8, 249, 1952).
Receptor Binding studies:
The following receptor binding studies, as well as the experimental
data reported below, establish compounds of the invention as
1-blockers, i.e. to be within a class of substances widely used as
antihypertensive and agents that can be used for the relief of
symptoms associated with obstructive disorders of the lower urinary
tract, including (but not limited to) benign prostatic hypertrophy
(BPH). See, e.g., Frishman, W. H. et al., Medical Clinics of N.
America, 72, 427, 1988 and references cited therein. Moreover, as
phenylpiperazines (and many compounds containing this structure)
can be good ligands for G protein coupled receptors such as the
.alpha.2, 5-HT.sub.1a and D.sub.2 receptors (see for example: Russo
F. et al. J. Med. Chem., 34, 1850, 1991), the affinity of the
compounds of the present invention for these different receptors
has been evaluated, in vitro, utilizing the receptor binding
technique.
Suzuki et al. Jap. J. Pharmacol. 58 (Suppl. 1):173P (1992) have
characterized the subtype of the .alpha..sub.1 receptor of human
prostate as .alpha..sub.1A. If this characterization is correct,
then a high affinity for the .alpha..sub.1A receptor would be
desirable for compounds active on the lower urinary tract and
especially on the prostate.
What is undesirable for compounds selective for the lower urinary
tract is an affinity for the .alpha..sub.2 and D.sub.2 receptor.
Such affinity is also undesirable for compounds with selectivity
for the 5HT.sub.1A receptors and for compounds to be used as
antihypertensives.
[.sup.3 H]prazosin binding (.alpha..sub.1 receptors)
Rat cerebral cortices were homogenized in 50 volumes of original
wet weight of ice-cold 50 mM Tris-HCl buffer pH 7.4. The
homogenates were centrifuged at 48,000.times.g for 10 minutes, and
the pellets were resuspended in the same volume of ice-cold buffer,
centrifuged and resuspended two more times. The final pellets
obtained were resuspended in 100 vols of 50 mM Tris-HCl buffer
(containing 0.1% ascorbic acid and 10 .mu.M pargyline) pH 7.4 and
incubated (1 ml/sample) for 30 min at 25.degree. C. with 0.35 nM
[.sup.3 H]prazosin, in absence or presence of 5-10 concentrations
of the displacing compound to be tested. Non specific binding was
determined in the presence of 2 .mu.M prazosin. h e incubations
were terminated by rapid filtration through Whatman GF/B filters
using a Brandel cell harvester and the filters were washed with
3.times.3 ml of ice-cold buffer. The radioactivity retained on the
filters was determined by liquid scintillation counting.
[.sup.3 H]prazosin binding (.alpha..sub.1A receptors).
Rat hippocampi were homogenized in 50 volumes of original wet
weight of ice-cold 50 mM Tris-HCl buffer pH 7.4. The homogenates
were centrifuged at 48,000.times.g for 10 minutes, the pellets were
resuspended in the same volume of ice-cold buffer and preincubated
for 30 min at 37.degree. C. with 10 .mu.M chloroethylclonidine
(CEC). The homogenates were centrifuged and resuspended in Tris-HCl
buffer two more times. The final pellets obtained were resuspended
in 80-120 vols of Tris-HCl buffer (containing 0.1% ascorbic acid
and 10 .mu.M pargyline) and incubated (2 ml/sample) for 30 min at
25.degree. C. with 0.25-0.35 nM [.sup.3 H]prazosin, in absence or
presence of 10 concentrations of the displacing compound to be
tested. Non specific binding was determined in the presence of 10
.mu.M phentolamine. The incubations were terminated by rapid
filtration through Whatman GF/B filters using a Brandel cell
harvester and the filters were washed with 3.times.3 ml of ice-cold
buffer. The radioactivity retained on the filters was determined by
liquid scintillation counting.
[.sup.3 H]prazosin binding (.alpha..sub.1B receptors).
Rat liver was homogenized in 50 volumes of original wet weight of
ice-cold 50 mM Tris-HCl buffer pH 7.4 and filtered through four
layers of cheesecloth. The homogenates were centrifuged at
48,000.times.g for 10 minutes, and the pellets were resuspended in
the same volume of ice-cold buffer, incubated for 30 minutes at
37.degree. C., centrifuged and resuspended two more times. The
final pellets obtained were resuspended in the same volume of
Tris-HCl buffer pH 7.4 (containing 0.1% ascorbic acid and 10 .mu.M
pargyline) and incubated (2 ml/sample) for 30 min at 25.degree. C.
with 0.4-0.6 nM [.sup.3 H]prazosin in absence or presence of 5-10
concentrations of the displacing compound to be tested. Non
specific binding was determined in the presence of 10 .mu.M
phentolamine. The incubations were terminated by rapid filtration
through Whatman GF/B filters using a Brandel cell harvester and the
filters were washed with 3.times.3 ml of ice-cold buffer. The
radioactivity retained on the filters was determined by liquid
scintillation counting.
[.sup.3 H]rauwolscine binding (.alpha..sub.2 receptors)
Rat cerebral cortices were homogenized in 50 volumes of original
wet weight of ice-cold 50 mM Tris-HCl buffer pH 7.4. The
homogenates were centrifuged at 48,000.times.g for 10 minutes, and
the pellets were resuspended in the same volume of ice-cold buffer,
incubated for 15 minutes at 37.degree. C., centrifuged and
resuspended two more times. The final pellets obtained were
resuspended in 100 vols of 50mM Tris-HCl buffer (containing 0.1%
ascorbic acid and 10 .mu.M pargyline) pH 7.4 and incubated (1
ml/sample) for 30 min at 25.degree. C. with 0.7-1.0 nM [.sup.3
H]rauwolscine, in absence or presence of 5-10 concentrations of the
displacing compound to be tested. Non specific binding was
determined in the presence of 10 .mu.M phentolamine. The
incubations were terminated by rapid filtration through Whatman
GF/B filters using a Brandel cell harvester and the filters were
washed with 3.times.3 ml of ice-cold buffer. The radioactivity
retained on the filters was determined by liquid scintillation
counting.
[.sup.3 H]spiperone binding (D.sub.2 receptors)
Rat striata were homogenized in 20 volumes of original wet weight
of ice-cold 50 mM Tris-HCl buffer pH 7.4, diluted to 30 vols and
centrifuged at 48,000.times.g for 10 minutes. The pellets were
resuspended in the 200 vols of 50 mM Tris-HCl buffer (containing:
120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1mM MgCl.sub.2, 0.1% ascorbic
acid and 10 .mu.M pargyline) pH 7.4 and incubated (1 ml/sample) for
15 min at 25.degree. C. with 0.3 nM [.sup.3 H]spiperone, in absence
or presence of 5-10 concentrations of the displacing compound to be
tested. Non specific binding was determined in the presence of 1
.mu.M (+)butaclamol. The incubations were terminated by rapid
filtration through Whatman GF/B filters using a Brandel cell
harvester and the filters were washed with 3.times.3 ml of ice-cold
buffer. The radioactivity retained on the filters was determined by
liquid scintillation counting.
[.sup.3 H]8-OH-DPAT binding (5HT.sub.1A receptors)
Rat hippocampi were homogenized in 50 volumes of original wet
weight of ice-cold 50 mM Tris-HCl buffer pH 7.4. The homogenates
were centrifuged at 48,000.times.g for 10 minutes, and the pellets
were resuspended in the same volume of ice-cold buffer, incubated
for 10 minutes at 37.degree. C., centrifuged and resuspended two
more times. The final pellets obtained were resuspended in 100 vols
of 50 mM Tris-HCl buffer (containing 0.1% ascorbic acid and 10
.mu.M pargyline) pH 7.4 and incubated (1 ml/sample) for 30 min at
25.degree. C. with 1 nM [.sup.3 H]8-OH-DPAT, in absence or presence
of 5-10 concentrations of the displacing compound to be tested. Non
specific binding was determined in the presence of 10 .mu.M 5-HT.
The incubations were terminated by rapid filtration through Whatman
GF/B filters using a Brandel cell harvester and the filters were
washed with 3.times.3 ml of ice-cold buffer. The radioactivity
retained on the filters was determined by liquid scintillation
counting. These receptor binding studies serve to establish
compounds of the present invention as ligands for the 5HT.sub.1A
receptor. As previously reported, compounds that are 5HT.sub.1A
ligands exert anxiolytic and antidepressant effects in animals and
humans (Hamon, M. et al., Ann. N.Y. Acad. Sci., 600, 114, 1990;
Traber J. et al., T.I.P.S., 8, 437, 1987). In all binding studies
the samples were run in triplicate. All the compounds were
initially tested at 1.times.10.sup.-6 M concentration, and in
presence of significant displacing activity, a complete competition
curve was generated (down to a concentration of 10.sup.-11 M). The
competition curves were always analyzed (to evaluate the IC.sub.50
values) by non linear curve fitting of the logistic equation
according to the method reported by De Lean et al. (Am. J.
Physiol., 235, E97, 1978), utilizing the ALLFIT program (publicly
available from the National Institute of Health (N.I.H.) Bethesda,
Md., USA) written for the IBM PC.
K.sup.+ -induced contractions of rat bladder strips:
The whole bladder of the rat was removed and immediately placed in
Krebs solution warmed at 37.degree. C. Strips of detrusor muscle
(20-30 mm long, 1-2 mm wide), were cut from the dome of the
bladder. Each strip was placed in a 10 ml organ bath and connected,
under a constant load of 1 g, to an isometric strain gauge (DY-1
Basile, Comerio, Varese, Italy). Contractions were recorded by
means of a Basile 7070 polygraph. After a 60 minute equilibration
period the strips were exposed to 80 mM KCl (final concentration).
This produced a rapid phasic contraction followed by a slow ensuing
and sustained tonic component. When the tonic contraction was
stable, the strips were washed and 30 minutes later a new
contraction was induced. After having recorded two or more
reproducible responses, one concentration of the tested compounds
was added to the bath and 30 minutes later a new contraction was
induced. The experimental groups consisted of at least two
preparations taken from different animals for each concentration of
compound tested. The IC50 values of inhibition of agonist-induced
contractions were evaluated by linear regression analysis.
Effects on noradrenaline-induced mortality in rats
Groups of 10 rats, fasted overnight, were intravenously (caudal
vein) treated with different doses of the tested compounds, 30
minutes before the injection of 0.6 mg/kg i.v. noradrenaline (2
ml/kg). This dose of noradrenaline induced a 100% of mortality in
the control animals within a few minutes. Survival rate after 24
hours was used as the evaluation criterium for efficacy of the test
compound. ED50 values (compound's dose that prevent the death in
the 50% of the animals treated with noradrenaline) and confidence
limits were obtained by the method of Bliss (Q. J. Pharm.
Pharmacol. 11, 192, 1935) by utilizing the percentage of survival
for each dose-level of the compound tested. The aim of the study
was to evaluate the in vivo alpha-antagonistic activity of the
compounds by utilizing the inhibition of mortality induced by
noradrenaline in rats as reported by Janssen et al. (Arzneim.
Forsch., 15, 104, 1965).
Hypotensive effect in normotensive rats
The animals were anaesthetized with pentobarbital sodium (50 mg/kg
i.p. for induction and, 30 minutes later, 50 mg/kg s.c. for
maintenance of anaesthesia). The left jugular vein was cannulated
with a polyethylene cannula (PE 50) for the intravenous compound
administration. The right carotid artery was cannulated with a
polyethylene cannula, filled with heparin (50 U.I., 0.4 ml/rat),
for the measurement of arterial blood pressure. In order to measure
the systolic and diastolic blood pressure, the arterial catheter
was connected to pressure transducer and recordings were made on a
San-ei Rectigraph polygraph. After a stabilizing period following
surgical procedure (30 min), in which arterial pressure was
continuously monitored, the compounds were administered in single
doses. Each dose of each compound was tested in a single animal.
Groups of 3-4 animals for each dose were used. Systolic and
diastolic blood pressure were continuously recorded before and
after compound administration, and quantified manually from the
polygraph tracing. All values were expressed as mean.+-.S.E. The
statistical significance of the difference in systolic and
diastolic blood pressure (SBP, DBP) values before and after
treatment was analyzed by Student's t test for paired data. In
order to compare the effects of the compounds, dose-response curves
(log dose transformation) were constructed by computing the percent
decrease in diastolic blood pressure at the peak effect. Regression
was considered significant when the correlation coefficient showed
P>0.01, using analysis of variance. Linear regression equations
were used in order to evaluate the theoretical effectiveness as
ED.sub.25 (the effective dose inducing a 25% decrease in diastolic
blood pressure, with 95% confidence limits).
Effects on Urethral Contractions (induced by noradrenaline
injection) and Blood Pressure in Dogs. after i.v.
administration
The experiments were performed according to the method of Imagawa
et al. (J. Pharmacol. Methods, 22, 103-111, 1989), with substantial
modifications, as follows: adult male beagle dogs, weighing 8-10
kg, were anaesthetized with pentobarbital sodium (30 mg/kg i.v. and
2 mg/kg/h i.v.), intubated and spontaneously ventilated with room
air. In order to monitor systemic blood pressure (BP), a PE
catheter was introduced into the aortic arch through the right
common carotid artery. A collateral of the left femoral vein was
cannulated for infusion of anaesthetic, and the right femoral vein
was cannulated for administration of compounds. For intraarterial
(i.a.) injection of noradrenaline (NA), a PE catheter was
introduced into the lower portion of abdominal aorta via the right
external iliac artery. Through such procedure, NA was selectively
distributed to the lower urinary tract. Via a midline laparotomy,
the urinary bladder and proximal urethra were exposed. In order to
prevent the filling of the bladder, the two ureters were cannulated
and the urine led outside. In order to record the prostatic
urethral pressure, a Mikro-tip catheter (6F) was introduced into
the bladder via the external urethral meatus, and withdrawn until
the pressure transducer was positioned in the prostatic urethra. A
ligature was secured between the neck of the bladder and urethra to
isolate the response of the latter and avoid any interaction with
the bladder. Another ligature was put around the Mikro-tip catheter
at the external urethral meatus, to secure the catheter itself.
After a stabilizing period following surgical procedure (30 min),
in which arterial and prostatic urethral pressure were continuously
monitored as basal values, i.a. administration of NA was made at
intervals of 10 min. The dose of NA chosen was such to produce an
increase of at least 100% in urethral pressure. The test compounds
were administered i.v. in a cumulative manner with intervals of
15-20 min between administrations. I.a. injections of NA were
repeated approximately 5 min. after every dosing of test compound.
Dose response curves were constructed computing the percentage
inhibition to the increase in urethral pressure (NA induced), and
the percentage drop in blood pressure produced by the test
compound. ED.sub.25 for diastolic blood pressure (dose inducing a
25% decrease) and ID.sub.50 (dose inducing a 50% inhibition of
NA-induced increase in urethral pressure) were computed by means of
linear regression analysis.
Effects on urethral contractions (induced by hypogastric nerve
stimulation) and blood pressure in dogs after i.v. and i.d.
administration
The animals were anaesthetized with pentobarbital sodium (30 mg/kg
i.v. for induction and 5 mg/kg/h i.v. for maintenance), intubated
and spontaneously ventilated with air room. Systemic blood pressure
was monitored via a Mikro-tip 6F pressure transducer introduced
into the aortic arch through the right common carotid artery. A
collateral of the left femoral vein was cannulated with a PE
catheter for infusion of the anaesthetic. A paramedian vertical
suprapubic incision extending from the base of the pelvis to the
mid-abdominal region was made and the bladder and the prostate were
exposed. The bladder was manually emptied with a syringe. The
hypogastric nerve was freed from the surrounding tissue and cut 1
cm distal from the inferior mesenteric ganglion. The distal end of
right or left branch of the nerve was placed on a bipolar platinum
electrode. Prostatic urethral pressure was monitored with a
Mikro-tip catheter (5F) introduced into the bladder via the
external urethral meatus, and withdrawn until the pressure
transducer was positioned in the prostatic region of the urethra. A
ligature was secured between the neck of the bladder and urethra to
isolate the response of the latter and to avoid any interaction
with the bladder. Another ligature was put around the Mikro-tip
catheter at the external meatus, to secure the catheter itself. For
intravenous administration of test compounds a collateral of the
right femoral vein was cannulated with PE catheter. For
intraduodenal administration, the duodenum was isolated and exposed
via a second abdominal laparotomy and cannulated for compound
administration. Intravenous administration: hypogastric nerve
stimulation were made with a train of rectangular pulses of 10-15
V, 10-30 Hz, width 5 msec, 8 sec duration. After a stabilizing
period following surgical procedure (30 min.) in which both
arterial and prostatic urethral pressure were continuously
monitored, five or more stimulations of the hypogastric nerve were
made at intervals of 10 min, and the mean of the urethral responses
considered as basal increase of urethral pressure. The compounds
were administered in cumulative way with intervals of 15 min among
the doses. Hypogastric nerve stimulation was repeated 5 min after
each dose. Intraduodenal administration: hypogastric nerve
stimulation were made with a train of rectangular pulses of 10 V,
10-30 Hz, width 5 msec, 7 sec duration. After a stabilizing period
following surgical procedure (30 min.) in which both arterial and
prostatic urethral pressure were continuously monitored, five or
more stimulations of hypogastric nerve were made at intervals of 15
min, and the means of urethral responses considered as basal
increase of urethral pressure. After administration of the
compounds, stimulations of urethra were performed from 15 up to 270
min, with intervals of 15 min in the first hour, and intervals of
30 min in the following hours. The statistical significance of the
differences after treatments vs basal values was analyzed by
one-way or two-way ANOVA and Dunnett's test. In order to compare
the effects of the administered compound, dose response curves (log
dose transformation) were constructed by computing, at the peak
effect, the percent decrease in diastolic blood pressure and the
percent inhibition of the increase in urethral pressure induced by
hypogastric nerve stimulation. Linear regression equations were
then used in order to evaluate the theoretical effectiveness as
ED.sub.25 (the effective dose inducing a 25% decrease in diastolic
and systolic blood pressure with 95% confidence limits) and
ID.sub.50 (dose inhibiting by 50% the increase in urethral
pressure, with 95% confidence limits). After the i.d.
administration, in order to evaluate the time course of the effects
on urethral and blood pressure, AUC.sub.0-270 min (area under the
inhibition curve for the urethral pressure) and AOC.sub.0-270 min.
(area over the hypotensive curve for diastolic blood pressure),
were computed by means of trapezoidal rule. For the urethral
pressure the ED.sub.50 AUC.sub.0-270 min was then computed by
linear regression analysis. ED.sub.50 AUC.sub.0-270 min represents
the oral dose requested to produce a theoretical inhibition of 50%
in area under the inhibition curve in the time considered.
Effects on noradrenaline-induced contractions of urethra and on
blood pressure in rabbits after i.v. administration
The animals were anaesthetized with pentobarbital sodium (20 mg/kg
i.v.) and urethane (1.2 g/kg i.v.), intubated and spontaneously
ventilated with air room. Systemic blood pressure was monitored via
a Mikro-tip 6F pressure transducer introduced into the aortic arch
through the right common carotid artery. A paramedian vertical
suprapubic incision extending from the base of the pelvis to the
mid-abdominal region was made and the bladder and the prostatic
portion of the urethra were exposed. The bladder was manually
emptied with a syringe. Prostatic urethral pressure was monitored
with a Mikro-tip catheter (5F) introduced into the bladder via the
external urethral meatus, and withdrawn until the pressure
transducer was positioned in the prostatic region of the urethra. A
ligature was secured between the neck of the bladder and urethra to
isolate the response of the latter and to avoid any interaction
with the bladder. Another ligature was put around the Mikro-tip
catheter at the external meatus, to secure the catheter itself. The
jugular vein was cannulated with a PE catheter for injection of the
compound or noradrenaline. For intraarterial administration of
noradrenaline the right femoral artery was cannulated with a PE
catheter, advanced up to the lower portion of abdominal aorta.
Intraarterial administration of noradrenaline: after a stabilizing
period following surgical procedure (30 min) in which arterial and
prostatic urethral pressure were continuously monitored, five or
more injection of noradrenaline were made in the femoral artery at
intervals of 15 min, and the mean of urethral responses was
considered as basal increase of urethral pressure. Such procedure
allows NA to be selectively distributed in the lower urinary tract,
with very low effects on cardiovascular system. The dose of
noradrenaline chosen (3-10 .mu.g/kg) was such to produce an
increase of at least 80-100% in urethral pressure. The compounds
were administered in cumulative way with intervals of 15 min. among
the doses; NA stimulations were repeated 5 min after every dose.
Intravenous administration of noradrenaline: after a stabilizing
period following surgical procedure (30 min.) in which arterial
pressure was continuously monitored, five or more injections of
noradrenaline in the jugular vein were made at intervals of 10 min,
and the mean of systolic blood pressure responses considered as
basal increase of systolic pressure. The compounds were
administered in cumulative way with intervals of 15 min. among the
doses. NA stimulation were repeated 5 min after every dose.
In this protocol, the urethral pressure was not recorded, but all
the animals were submitted to the same surgical procedure as in
previous protocol. Linear regression equations were used in order
to evaluate the theoretical effectiveness as ID.sub.50 (dose
inhibiting 50% increase in urethral pressure and systolic blood
pressure, with 95% confidence limits) and ED.sub.25 (the effective
dose inducing a 25% decrease in diastolic blood pressure, with 95%
confidence limits). The effects on blood pressure (ED.sub.25 on
diastolic BP) were computed considering together the hypotensive
effects obtained in the two protocols.
Results
Compounds as prepared in the Examples were tested according to the
methods reported above, and the results are given in the Tables
below, together with comparative results for the reference
standards used. Compounds having receptor affinity (IC.sub.50
values) lower than about 500 nM are generally considered to have
good affinity. Compounds with IC.sub.50 values less than 100 nM are
generally preferred.
TABLE I
__________________________________________________________________________
K+ Stimulation Acute Toxicity of Rat Bladder Receptor Binding in
Mice IC.sub.50 (.mu.M) Compound IC.sub.50 (nM) LD.sub.50 (mg/kg)
Contractions Example No. .alpha..sub.1 5-HT.sub.1A i.p. p.o Phasic
Tonic
__________________________________________________________________________
4 550 55 346 732 >10 >10 5 20 19 621 >3000 >10 >10 6
107 1000 233 -- >10 >10 7 86 155 384 1915 -- -- 8 66 111
>500 1915 -- -- 9 27 18 620 >3000 -- -- 11 29 9 247 297 2.9
3.0 13 68 229 >1000 >3000 10.0 10.0 14 61 6 140 559 <10
<10 15 8 131 306 496 -- -- 16 220 1050 345 778 1.6 2.2 17 59 910
299 608 8.8 3.8 18 270 >1000 457 3000 -- -- 19 165 340 >1000
>3000 >10 >10 20 169 85 297 594 2.7 2.5 21 17 33 297 566
1.7 1.7 22 117 48 >500 >2000 -- -- 24 690 212 >1000
>3000 <10 <10 26 270 >1000 >500 >2000 <10
<10 27 23 124 399 >3000 1.0 0.8 28 120 96 203 1127 <10
<10 29 86 45 730 >3000 10.0 10.0 32 119 46 301 >2000 10.0
>10 33 17 38 399 >2000 10.0 10.0 34 30 34 >500 -- 2.8 3.6
35 15 8 329 959 10.0 10.0 36 18 54 >500 >2000 -- -- 37 32 77
>500 >2000 -- -- 38 20 344 >500 >2000 <10 <10 39
90 170 >1000 >3000 -- -- 40 75 83 140 349 0.5 0.9 41 43 53
399 2241 0.7 1.4 42 7 39 459 2163 10.0 10.0 43 166 >1000 -- --
-- -- 44 685 201 84 399 0.6 0.5 45 15 106 329 1727 <10 <10 46
86 23 -- -- -- -- 47 36 23 330 1047 2.7 5.2 48 104 5 500 1914
<10 <10 49 152 9 432 >2000 <10 <10 50 39 300 211 299
>10 <10 51 22 84 >500 >2000 -- -- 52 89 2 127 224
<10 <10 53 7 41 127 1020 -- -- 54 35 143 106 421 -- -- 55 291
>1000 128 >2000 <10 <10 56 25 748 >500 -- -- -- 57
69 >1000 500 >2000 -- -- 59 5 9 >500 278 -- -- 60 25 45
203 329 -- -- 61 36 11 315 592 -- -- 62 252 278 128 344 -- -- 63
194 99 309 479 -- -- 64 40 11 231 -- -- -- 65 113 26 -- -- -- -- 66
57 56 404 601 -- -- 67 4 4 508 1868 -- -- 68 29 13 -- -- -- -- 69
16 87 344 -- -- -- 70 53 85 >500 1868 -- -- 71 108 69 -- -- --
-- 72 145 111 479 >2000 -- -- 73 6 89 202 462 -- -- 74 178 482
-- -- -- -- 75 147 15 -- -- -- -- 77 6 127 >500 >2000 -- --
78 18 116 -- -- -- -- 79 77 141 >500 >2000 -- -- 80 28 162
411 -- -- -- 81 13 81 451 -- -- -- 83 30 5 -- -- -- -- 84 5 2 349
-- -- -- 85 16 14 >500 1138 -- -- 86 48 20 101 451 -- -- 87 119
107 237 >500 -- -- 88 216 11 -- -- -- -- 89 101 50 -- 43 -- --
90 54 18 388 -- -- -- 91 71 60 >500 -- -- -- 92 67 28 223 646 --
-- 93 47 38 375 2000 -- -- 94 39 66 >500 -- -- -- 95 16 170
>500 -- -- -- 96 19 155 >500 1434 -- -- 97 30 37 >500 1541
-- -- 98 34 12 >500 >2000 -- -- 99 44 5 310 2000 -- -- 100 17
1 500 >2000 -- -- 101 46 35 -- -- -- -- 102 56 18 -- -- -- --
103 31 33 91 206 -- -- 104 9 15 >500 -- -- -- 105 9 31 -- -- --
-- 106 9 12 -- -- -- -- 107 37 16 262 -- -- -- 108 26 52 -- -- --
-- 109 10 32 -- -- -- -- 110 26 15 327 -- -- -- 111 8 11 -- -- --
112 88 233 -- -- -- -- 113 16 1 -- -- -- -- 115 10.5 2 -- -- -- --
116 39 95 121 252 -- -- 117 47 134 >500 -- -- -- 118 148 28
>500 -- -- -- 119 51 36 -- -- -- -- 120 5 5 -- -- -- -- 122 138
90 -- -- -- -- 123 588 241 -- -- -- -- 124 60 7.5 -- -- -- -- 125
72 16 -- -- -- -- 126 11 2 >500 -- -- -- 128 74 739 >500 --
-- -- 129 59 37 299 -- -- -- 130 8 7.5 -- -- -- -- 131 18 46 -- --
-- -- 132 96 300 -- -- -- -- 134 43 1 -- -- -- -- 135 80 1542 -- --
-- -- 137 101 33 -- -- -- -- 141 72 37 -- -- -- -- 142 55 278 -- --
-- -- 143 39 3 >500 -- -- -- 144 71 34 >500 -- -- -- 145 19
63 >500 519 -- -- 146 75 150 >500 -- -- -- 147 786 >1000
>500 -- -- -- 148 24 29 -- -- -- -- 149 20 27 -- -- -- -- 150 17
73 500 -- -- -- 151 21 868 >500 -- -- -- 152 13 18 306 -- -- --
153 43 27 -- -- -- -- 155 30 17 >500 683 -- -- 156 140 44 -- --
-- -- 157 332 792 -- -- -- -- 158 102 226 -- -- -- -- 159 16 14 --
-- -- -- 160 352 542 -- -- -- -- 161 8 10 -- -- -- -- 168 138 186
-- -- -- -- 169 5 26 >500 -- -- -- Flavoxate >>1000
>>1000 385 808 13 13
__________________________________________________________________________
TABLE II ______________________________________ Compound Receptor
Binding Example IC.sub.50 (nM) No. .alpha..sub.1A .alpha..sub.1B
.alpha..sub.2 D.sub.2 ______________________________________ 4 --
-- -- 309 5 9 28 -- 53 6 -- -- -- 138 7 46 76 -- 364 8 17 37 -- 421
11 2 24 128 161 13 14.5 79 275 349 14 20 165 -- 163 15 2 7 -- 655
16 -- -- -- 939 17 21 34 313 390 18 -- -- -- 412 19 -- -- -- 413 20
-- 68 -- 412 21 3 12 15 44 22 -- -- -- 228 24 -- -- -- 483 26 -- --
-- >1000 27 5 31 18 83 28 -- -- -- 72 29 -- 125 -- 92 32 -- --
-- 236 33 8. 5 178 -- 60 34 32 62 -- 42 35 12 14 -- 97 36 8 74 --
562 37 5 5 -- 187 38 15 49 -- 460 39 39 311 -- 483 40 5 25 53 60 41
10 39 64 46 42 6 16 73 67 43 -- -- -- >1000 44 -- -- -- 796 45
-- 53 -- 169 46 23 49 -- 69 47 14 55 182 193 48 82 184 -- 45 49 21
389 -- 592 50 8.5 38 -- 576 51 1.5 24 22 57 52 7.1 188 -- 103 53
0.4 5.5 25 78 54 23 44 -- 1054 55 322 291 -- >1000 56 8 16 -- 15
57 52 43 -- 446 58 -- -- -- 4419 59 0.5 5 -- 1000 60 17 23 -- 90 61
32 49 -- 17 62 -- -- -- >1000 63 -- -- -- >1000 64 9 259 --
317 65 101 207 -- 315 66 63 138 -- 134 67 2 8 -- 7 68 -- 61 -- 68
69 4 23 -- 130 70 -- 137 -- 34 71 59 165 -- 1000 72 -- -- -- 106 73
2 18 -- 83 74 -- -- -- 1000 75 -- -- -- 131 77 1 29 -- 270 78 5 18
-- 65 79 48 375 -- 299 80 29 52 -- 563 81 8 27 -- 69 83 1 60 -- 81
84 2 15 -- 75 85 2 56 -- 492 86 4 44 -- 265 87 38 61 -- 801 88 26
244 -- 2223 89 -- 43 -- 281 90 13 33 -- 201 91 8 50 -- 117 92 16 49
-- 222 93 23 41 -- 238 94 3 25 -- 195 95 11 32 -- 209 96 7 51 --
158 97 6 74 -- 287 98 4 69 -- 59 99 52 36 -- 781 100 1 145 -- 455
101 3 283 -- 548 102 11 48 -- 1288 103 1.5 138 -- 179 104 1 45 7 67
105 3 46 -- 172 106 1 51 -- 196 107 3 59 -- 179 108 6 36 -- 390 109
1 21 -- 673 110 1 32 -- 655 111 1 66 -- 398 112 -- 223 -- 105 113 1
42 -- 303 115 6 35 60. 5 640 116 29 42 -- 224 117 8 17 -- 349 118
18 304 -- 526 119 3 167 -- 2414 120 1 5.5 -- 1627 122 -- -- -- 73
123 -- -- -- 1759 124 6 104 -- 454 125 6.5 174 -- 766 126 5 57 --
275 128 6 52 -- 127 129 27 43 -- 41 130 3 21 -- 17 131 21 123 --
387 132 -- 144 -- 541 134 3.5 64 -- 23 135 -- -- -- 368 137 50 --
155 141 1 51 -- 225 142 45 89 -- 183 143 16 23 -- 878 144 -- 63 --
287 145 13 19 -- 1102 146 45 67 -- 1421 147 -- -- -- 3613 148 7 46
-- 434 149 -- 40 -- 213 150 -- 26 -- 27 151 -- 35 -- 605 152 1 108
-- 34 153 -- 73 -- 42 155 -- 114 -- 545 156 -- 129 -- 585 157 -- --
-- 298 158 79 482 -- 497 159 -- 30 -- 199 160 -- 430 -- 2012 161 3
7 -- 207 168 67 560 -- 789 169 3 13 -- 37
______________________________________
TABLE III ______________________________________ Compound
Na-induced mortality Hypotensive effect Example rat normotensive
rat No. ED.sub.50 (.mu.g/kg i.v.) ED.sub.25 (.mu.g/kg i.v.)
______________________________________ 5 1000 191 11 8 45 13 399 87
15 111 284 17 1260 81 21 75 73 27 240 99 35 -- 198 36 148 32 37 312
-- 38 -- 44 40 170 69 41 766 543 42 171 1,3 3 45 548 513 47 3830
102 49 4220 415 50 212 125 51 410 100 53 77 >1000 54 -- 260 59
35 65 69 85 79 71 1000 400 73 15.5 >3000 77 34 -- 78 83 530 80
304 126 83 74 271 84 270 >3000 85 24 44 86 33 216 93 457 -- 94
-- 22 99 194 >1000 100 15.5 -- 104 3 174 106 -- 157 107 212 306
109 -- 187 111 22 260 113 11 -- 115 33 38 116 690 151 120 87 69 134
40 -- 136 >3000 -- 141 7.5 -- 145 27 146 152 6 --
______________________________________
TABLE IV ______________________________________ Effects on Urethal
Contractility (NA-induced contraction) and Blood Pressure in Dogs
Compound Urethra DBP Example ED.sub.50 ED.sub.25 DBP/Urethra No.
(.mu.g/kg i.v.) (.mu.g/kg i.v.) ratio
______________________________________ 5 37.0 1074 29.0 11 1.4 390
278.6 13 16.0 215 13.4 15 10.1 65.6 6.5 17 10.0 6.2 0.6* 21 6.6 127
19.2 27 3.2 9.8 3.1* 40 11.0 152 13.8 41 57.0 745 13.1 42 31.0 404
13.0 45 16.4 186 11.3 47 35.0 530 15.1 49 260.0 2150 8.3 51 8.6 327
38.0 53 8.1 113 13.9 59 5.7 141 24.7 69 14.7 156.5 10.4 73 3.5 110
31.4 83 9.7 134 13.8 100 9.2 296 32.2 104 1.8 96.7 53.7 113 6.9 113
16.4 115 1.4 126 90.0 116 21.0 264 12.6 Prazosin 3.6 6.6 1.8*
Terflavoxate >10000 6060 --
______________________________________ Urethra: active dose in
inhibiting by 50% the noradrenaline induced contraction of urethra
DBP: active dose in lowering diastolic blood pressure by 25%
DBP/urethra: ratio between the active doses (selectivity index)
*nonselective: substantial effect on both urethra and DBP.
TABLE V ______________________________________ Effects on Urethral
Contractility (hypogastric nerve stimulation - induced contraction)
and Blood Pressure in Dogs Compound Urethra DBP Example ED.sub.50
ED.sub.25 DBP/Urethra No. (.mu.g/kg i.v.) (.mu.g/kg i.v.) ratio
______________________________________ 11 3.2 76.9 24.0 Prazosin
10.2 10.0 1.0 ______________________________________
TABLE VI ______________________________________ Effects on Urethral
Contractility (hypogastric nerve stimulation - induced contraction)
and Blood Pressure in Dogs Compound Urethra DBP Example ED.sub.50
ED.sub.25 DBP/Urethra No. (.mu.g/kg i.v.) (.mu.g/kg i.v.) ratio
______________________________________ 11 53.0 1652 31.2 104 16.0
706 44.1 Tamsulosin 12.9 50 3.8
______________________________________
TABLE VI bis ______________________________________ Effects on
Urethral Contractility (hypogastric nerve stimulation - induced
contraction) and Blood Pressure in Dogs: % effect after 100
.mu.g/kg i.d. administration Compound Urethra DBP Example No. %
peak % AUC % peak % AOC ______________________________________ 11
63.4 47.6 6.6 3.6 59 68.9 43.2 7.7 5.0 77 42.8 21.6 4.9 2.4 80 62.9
36.2 7.4 3.4 85 66.5 44.4 7.5 5.8 111 82.7 52.9 6.9 4.0 115 78.3
56.1 7.9 8.2 120 43.8 17.5 4.6 1.3 141 69.8 52.5 7.6 2.9 145 61.1
35.4 6.2 3.7 152 67.1 52.3 12.0 9.0 Tamsulosin 94.0 86.8 34.4 25.2
______________________________________
TABLE VII ______________________________________ Effects on
Urethral Contractility (NA-induced contraction) and Blood Pressure
in Rabbits Compound Urethra DBP Example ED.sub.50 ED.sub.25
DBP/Urethra No. (.mu.g/kg i.v.) (.mu.g/kg i.v.) ratio
______________________________________ 11 5.5 36.9 6.7 tamsulosin
1.5 1.1 0.7 ______________________________________ Urethra: active
dose in inhibiting by 50% the contraction of urethra induced by
noradrenaline DBP: active dose in lowering diastolic blood pressure
by 25% DBP/urethra: ratio between the active doses (selectivity
index)
Effective Amounts
The following represent guidelines to effective oral, parenteral or
intravenous dose ranges expressed in mg/kg of body weight per day
for the following uses:
______________________________________ (a) In obstructive disorders
of the lower urinary tract: General 0.001-20 Preferred 0.05-1 Most
Preferred** 0.3 (b) As antihypertensives: General 0.01-20 Preferred
0.1-5 Most Preferred** 1 (c) As anxiolytics - antidepressants:
General 0.01-20 Preferred 0.05-5 Most Preferred** 0.5 (d) As
bladder spasmolytics: General 0.01-20 Preferred 0.02-10 Most
Preferred** 2 ______________________________________ **Most
preferred values refer to oral dosing. Intravenous dosages should
be 10 to 100 fold lower.
Patients in need of treatment by the present compounds and
compositions also include humans that have one or more depression
symptoms (as defined, e.g. in Harrison's Principles of Internal
Medicine, XII Ed., McGraw-Hill, Inc., p.2124) or humans that
display anxiety symptoms (Harrison's, supra, pp. 2131-2134).
Selective use dosages, i.e. dosages that are active in the lower
urinary tract without a substantial effect on the blood pressure,
depend on the particular compound employed. Generally, in the case
of a compound selective in inhibiting urethral contraction, up to
four times the amount of the ED.sub.50 used in inhibiting urethral
contraction can be administered without substantial effect on blood
pressure. Further refinements and optimization of dosages are
possible using no more than routine experiments. The active
compounds of the invention may be orally administered, for example,
with an inert diluent or with an edible carrier, or they may be
enclosed in gelatin capsules, or they may be compressed into
tablets. For the purpose of oral therapeutic administration, the
active compounds of the invention may be incorporated with
excipients and used in the form of tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, chewing gum and the like.
These preparations should contain at least 0.5% of active
compounds, but the amount of active ingredient may be varied
depending upon the particular form and may conveniently be between
5% to about 70% of the weight of the unit. The amount of active
compound in such compositions is such that a suitable dosage will
be obtained although the desired dosage can be obtained by
administering a plurality of dosage forms. Preferred compositions
and preparations according to the invention are prepared so that an
oral dosage unit form contains between 1.0-300 milligrams of active
compound. The tablets, pills, capsules, troches and the like may
also contain for example the following ingredients: a binder such
as micro-crystalline cellulose, gum tragacanth or gelatin; an
excipient such as starch or lactose, a disintegrating agent such as
alginic acid, sodium starch glycolate, cornstarch and the like; a
lubricant such as magnesium stearate or hydrogenated castor oil, a
glidant such as colloidal silicon dioxide; and a sweetening agent
such as sucrose or saccharin may be added or a flavoring agent such
as peppermint, methyl salicylate, or orange flavoring. When the
dosage unit form is a capsule, it may contain, in addition to
materials of the above type, a liquid carrier such as a fatty oil.
Other dosage unit forms may contain other various materials which
modify the physical form of the dosage unit, for example, as
coatings. Thus, tablets or pills may be coated with sugar, shellac,
or other enteric coating agents. A syrup may contain, in addition
to the active compounds, sucrose as a sweetening agent and certain
preservatives, dyes, coloring and flavors. Materials used in
preparing these various compositions should be pharmaceutically
pure and nontoxic in the amounts used. For the purpose of
parenteral therapeutic administration, the active compounds of the
invention may be incorporated into a solution or suspension. These
preparations should contain at least 0.1% of active compound, but
may be varied between 0.5 and about 30% of the weight thereof. The
amount of active compound in such compositions is such that a
suitable dosage will be obtained. Preferred compositions and
preparations according to the present inventions are prepared so
that a parenteral dosage unit contains between 0.2 to 100
milligrams of active compound. The solutions or suspensions may
also include the following components: a sterile diluent such as
water for injection, saline solution, fixed oils, polyethylene
glycols, glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylenediamine tetraacetic acid; buffers such as
acetates; citrates or phosphates and agents for the adjustment of
tonicity such as sodium chloride or dextrose. The parenteral
multiple dose vials may be of glass or plastics material.
Additional compositions suitable for administration by various
routes and containing compounds according to the present invention
are also within the scope of the invention. Dosage forms,
additional ingredients and routes of administration contemplated
herein include those disclosed in U.S. Pat. Nos. 4,089,969; and
5,091,182, all incorporated by reference in their entirety.
* * * * *